Published in the Bulletin of Experimental Treatments for AIDS April 1999 issue, by the San Francisco AIDS Foundation.

Related BETA Article:
Nuts and Bolts of Clinical Trials

April 1999 Table of Contents

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Volunteering for Clinical Trials

By Bruce Mirken

The array of drugs now available to treat HIV infection and its associated conditions is the product of many hundreds of clinical trials involving tens of thousands of volunteers, if not more. As HIV/AIDS treatment has evolved, so has HIV-related research. With many approved treatments now available, researchers are finding it harder to recruit volunteers and are working to make their studies more "user-friendly" (see "Current Challenges to HIV Research" in this issue of BETA for another perspective on this topic). In addition, more trials are being designed to study treatment strategies as opposed to individual drugs.

Clinical Trial Basics

This article will focus primarily on clinical trials. A clinical trial is an experiment conducted with voluntary human subjects, designed to test a drug, vaccine, or medical procedure. Before these trials begin, experimental treatments receive extensive preclinical testing in the laboratory and on animals. Many treatments never reach the clinical trial stage because preclinical testing suggests they either will not be effective or are not safe to use on humans.

Although this article will primarily consider clinical trials, it is worth noting that there are other kinds of clinical research. For example, observational studies do not test a particular drug or vaccine but simply involve observing large numbers of volunteers in an attempt to glean information from their experiences. Some of the results may reveal useful information regarding a drug or combination of drugs. There is little risk in volunteering for an observational study other than the possible inconvenience of periodic tests or interviews, but neither is there the potential benefit of being among the first to use a promising new drug.

After laboratory and animal testing have been completed and the agent appears promising, human testing begins. Testing of drugs and vaccines is divided into three phases: phase I studies are the first human trials of a new product. They are most often small (usually involving 20-100 volunteers) and short-term, designed primarily to see if the drug is safe. Phase I studies are generally done on healthy volunteers (for instance, phase I HIV vaccine trials are performed on HIV negative people at low risk for acquiring HIV infection).

They are commonly designed as dose-escalation or dose-ranging studies, in which researchers start with very low doses and gradually work up to higher doses in succeeding groups of patients, in an effort to determine what doses can be given safely. Phase I studies also look at a drug's "pharmacokinetics": how the drug behaves in the body, what levels it reaches in the blood and tissues, how rapidly it is eliminated, etc.

The Food and Drug Administration (FDA) estimates that approximately 70 out of every 100 drugs pass phase I and go on to further testing. However, simply making it through phase I does not guarantee that a drug is completely safe. While these small, short trials are likely to catch toxicities that show up quickly and are common, some drugs cause serious problems that may take a long time to appear or may occur in only a small proportion of people. Such effects are not usually seen during phase I.

Phase II studies are the first trials that determine a drug or vaccine's efficacy--that is, whether the agent does what it is proposed to do. Phase II studies are larger and longer than phase I studies, and they also generate important safety information. If phase II is successful, the product will go on to large phase III trials, designed to give sufficient proof of efficacy for the FDA to approve it for sale. Occasionally researchers will attempt to speed the process by designing studies that aim to accomplish the work of two phases at once, e.g., a phase I/II trial.

The study plan or blueprint is called the protocol. It describes what will be tested, on whom it will be tested, specific inclusion and exclusion criteria, and how the research will be done. In most studies the volunteers are divided into groups or "arms." Typically, one group receives the drug or vaccine being tested.

Another group, called a control arm, receives either the standard treatment for the condition (if one exists) or no treatment. Often, people in the control arm receive a placebo or "sugar pill," an inactive substance made to look like the product being tested. Results from the control arm are compared with those from the treatment arm as part of the process of evaluating the effects of the drug.

Studies are often randomized, meaning that volunteers are assigned to the various arms by random chance. Randomization is used to make sure that no bias on the part of the researchers affects which volunteers form each group. Also to avoid bias, studies are commonly blinded, meaning that the volunteers do not know if they are receiving the new treatment. In a double-blind study, neither the researchers nor the volunteers know who is receiving the new treatment. The opposite of this is an open-label study, in which everyone involved knows who is getting what treatment.

Participation in clinical trials is based on the principle of informed consent. This means that participants have the right to choose freely whether or not to volunteer, and to make that choice after all of the study procedures, as well as the potential risks and possible benefits, have been explained. Federally funded trials must follow specific informed consent guidelines, and many states have laws regarding such guidelines.

Participants are always asked to sign an informed consent document before participating in a trial, meaning that they understand the procedures and risks, but signing is not binding; participants can decide to quit at any time. If new information becomes available while the study is in progress, particularly regarding safety issues, it should be provided to participants, who then may be asked to sign a new informed consent document.

Primary Considerations

Years ago persons with AIDS (PWAs) commonly volunteered for drug trials as a means of gaining access to potential treatments for HIV/AIDS that were literally unavailable elsewhere. That picture has changed dramatically in recent years, notes Matthew Sharp, AIDS treatment educator at the Asian & Pacific Islander Wellness Center. Sharp previously worked at San Francisco General Hospital, recruiting members of minority communities to volunteer for HIV/AIDS studies. As a longtime activist with ACT UP/Golden Gate, he has also helped design trials and has volunteered for several clinical trials himself.

"Nowadays," he says, "I would be less apt to be in a clinical trial. Mostly the reason I was in them before was access: I needed the drugs. Now most of the drugs I need are available [on the open market]."

Having been on both sides of the fence, Sharp worries that research may be losing momentum. He observes "a kind of apathy...in some people in the community and some of the pharmaceutical companies, because of the sort of feeling that AIDS is over. The fact of the matter is there's still a lot we do not know." Current treatments are not effective for all patients or may require lifelong therapy. Sharp hopes people with HIV will continue to volunteer for studies out of a desire to increase knowledge and improve treatments, even if they do not have an urgent personal need for experimental drugs.

Sharp and others also emphasize that the decision to volunteer for research should not be made casually. It is a serious decision that should be made only after careful consideration of the possible risks, benefits, and inconvenience, in consultation with a knowledgeable health-care provider. "It takes a lot of commitment to be in a study," Sharp emphasizes. "You have to be willing to commit extra time for extra visits to the doctor, and for blood work that you have to have done. There may be side effects that are not known." In spite of the uncertainties, many volunteers enroll in clinical trials knowing that the information gained from results will help other HIV positive people in the future.

Making the Decision to Enroll

Information about AIDS trials in need of volunteers is relatively easy to find. Treatment newsletters and the gay press often carry notices of trials that are recruiting, and a number of telephone hotlines and Internet sites also provide information. (Some of these resources are listed at the end of this article.)

A prospective participant's first contact is likely to be with a research nurse or trial coordinator. Eventually all participants will meet with the physician conducting the trial, but most early interactions will be with these other staff. While the vast majority of those who work on clinical trials are professional, caring, honest, and respectful of the volunteers, it is important to remember that these individuals have a variety of responsibilities and obligations that may pull them in several directions at once. Part of their function is to recruit volunteers, and indeed the trial site's funding or its ability to conduct further trials may be endangered if recruitment falls short.

A group of researchers called the Project on Informed Consent (PIC) wrote in a December 1998 article in the Journal of the American Medical Association, "Financial pressures on researchers may influence the conduct of clinical trials, and there is concern that, in some settings, scientific investigators are compensated according to the number of subjects who complete protocols."

Although the rules and procedures designed to protect trial participants are extensive, some experts, like the members of the PIC, feel they need improvement. The result, says Jeff Getty, another longtime AIDS activist, is that "you have to look out for your own interests and be prepared to be your own advocate." Like Sharp, Getty has volunteered for many studies, helped design research, and experienced both the benefits and pitfalls firsthand.

He believes in getting as much information as possible before making a decision. Getty urges prospective trial volunteers to look at the actual study protocol, not just the informed consent document, and says, "You need to know exactly what it is that they're doing--your chances of getting active versus inactive drugs, reporting systems for side effects, how they're going to monitor you, and the risks."

While the informed consent document will describe potential risks, Getty argues that "you're going to see a better analysis of what's going on in the actual protocol." Sometimes pharmaceutical companies sponsoring studies are reluctant to release the full protocol, saying it contains proprietary business information, but Getty says it's worth asking to get a look.

Unlike the informed consent document, the protocol is usually written in highly technical language. Regular health-care providers can help explain these documents, and act as an important resource for people considering participating in a trial. Meg Newman, MD, who treats people with HIV at San Francisco General Hospital's Positive Health Clinic (formerly known as Ward 86), works closely with people who are thinking about volunteering.

"A trial has very different responsibilities and obligations and is a very different setup than a primary care relationship," she explains. "A study has the goal of trying to learn more about a specific question, and although it hopefully will be beneficial for the patient, it doesn't offer the patient the kind of long-term support he or she may need to make the best medical decisions." Research, in other words, is fundamentally different from ordinary medical care and must be approached accordingly. "What would concern me would be people entering clinical trials without a primary care physician, and I do not think [study participation] should be used in place of that," Newman emphasizes.

Newman says she has seen numerous studies that she would counsel people to avoid, either because she thought the trial was poorly designed or because it wasn't appropriate for a particular person. In some instances one's primary care physician might be the doctor conducting the study. Even in those cases, Newman says it is important for people to seek objective medical advice from a provider not involved in the trial. "They need to work with someone whose agenda is not research," she says. "They need an advocate."

Risks, Benefits, and Questions to Ask

Information obtained about a study and consultation with primary care providers can help individuals assess the risks and benefits of a trial. Those benefits may include early access to a useful new drug, testing and medical evaluations that might not otherwise be available, often under the supervision of experts in the field, and sometimes financial compensation. On the other hand, a new drug may prove useless or even harmful, participants might get a placebo, and required office visits and lab tests may take up considerable time. Although experimental drugs and the necessary tests should always be provided free of charge, participating in a study might involve expenses, such as transportation or childcare during appointments, that are not reimbursable.

Some questions to ask:

It might be a drug company, a government agency such as the National Institutes of Health (NIH), or some other organization or institution.

An IRB often reviews and approves protocols. While this doesn't guarantee that a trial is desirable, the absence of such approval is cause for serious concern.

Is it aimed at proving a new drug's safety (phase I)? Its efficacy (phase II/III)? Is the trial testing a new treatment strategy (combination of drugs) involving already approved drugs?

If a trial's schedule is a hardship, ask if there are ways to make it easier, such as assistance with transportation or flexibility in the scheduling of appointments. If the requirements of a trial will be difficult, consider whether participation is really going to be feasible.

Even if a drug has never been tested on humans, the researchers should be able to discuss what it is proposed to do and how it is believed to work. Tests on animals will give at least some indication of safety issues. Getty recalls inquiring about one drug study and finding that "they were a little concerned about the animal data because it had killed a couple of monkeys: it blew out their kidneys. After I saw the animal data I did not go into the study."

"If there are side effects, who will pay for evaluation and treatment?

Useful information about experimental treatments is often available from sources not associated with the trial. The resource guide lists a number of these. An experimental drug's possible drawbacks may include more than just side effects. For example, if a medication is in the same class as other drugs (such as protease inhibitors), it is possible that cross-resistance might make other drugs in that class less effective for later use. "I'd want people to imagine how it's going to fit in with how their disease is going and with their long-term treatment options," Newman explains. Any experimental drug that might close off options for future therapy should be approached with caution, though there may be circumstances where the risk seems worth it.

Other questions to ask include:

Some trials require volunteers to stop taking certain other medications, either due to safety concerns (for example, because of how the drugs might interact) or because the researchers want clean data untainted by the effects of other medicines.

"Whom do participants call if they have side effects or other problems?

It is important to know if a health-care professional can be reached quickly between appointments, including evenings and weekends, in case help is needed.

A Data and Safety Monitoring Board (DSMB) periodically reviews ongoing trials for safety concerns and to detect early significant benefits in the treatment arm(s). Many trial sites, including all the centers that form the federally funded AIDS Clinical Trials Group (ACTG), have Community Advisory Boards (CABs), groups of patients, activists, and ordinary citizens who advise them on practical, ethical, and scientific issues. CABs have played an important role in making ACTG researchers more sensitive to the needs of patients in their studies.

If a drug is beneficial, participants may want to continue taking it after the trial concludes. Many studies make provisions for such drug continuation, often through follow-up or "rollover" trials for those who have successfully completed the protocol. Occasionally, however, subjects have had their supply of an experimental drug cut off at trial's end, even though it was benefiting them.

Common Dilemmas

It is important not to be intimidated or afraid to ask questions, Getty advises. If something has not been satisfactorily explained or some aspect of the trial feels uncomfortable, the patient should keep asking questions. Trouble getting satisfactory answers or being rushed or not listened to may be important warning signs. While most scientists are well-intentioned and competent, they are also human.

Unfortunately, studies with poor designs have sometimes put participants at needless risk. Recently, for example, a heavily criticized study called ACTG 343 put patients on AZT/3TC/indinavir for as little as six months, then switched some patients to weaker "maintenance" regimens in hopes that an undetectable viral load could be maintained. Treatment advocates argued that there was little evidence such an approach would work and that volunteers on the weakened regimens were being needlessly subjected to a risk of developing drug resistance. Just as they predicted, those on the maintenance regimens began seeing their viral loads rebound and the trial was stopped prematurely.

The ACTG 343 experience also illustrates the importance of having a clear understanding of a study before enrolling. At the time the trial was stopped, San Francisco physician David Senechek, MD, said he had a patient participating in the study who hadn't realized he could be switched to a weaker regimen. After going over the protocol, Senechek advised his patient to leave the trial, which he did.

Some would-be trial volunteers are faced with precisely the opposite predicament: a study that looks attractive, involving a drug they urgently want, but for which they do not qualify according to the study protocol. This can be particularly frustrating if the inclusion criteria seem arbitrary--a particular CD4 cell count or viral load number, for example--and especially if other treatment options are limited.

What to do? First, check to see if there is another mechanism for obtaining the drug. Many anti-HIV drugs are available via expanded access programs prior to FDA approval, and even those that are not are sometimes obtainable by patients without other treatment options under individual compassionate use protocols.

Some PWAs have submitted falsified lab results in order to be permitted to join a trial they otherwise would not qualify for. "It's a huge dilemma," Sharp comments. "But I honestly would have to say that after all my years of experience I would not recommend that people lie to be in a study, because I do not think it really does anybody any good." If scientists have false information on the people they are studying, he explains, they can draw incorrect conclusions from the data, potentially harming everyone who might eventually take the drug.

Giving false information in order to participate in a study can also be extremely dangerous, Sharp and Getty both note. For example, a participant's failure to disclose other drugs he or she is taking, or taking medications barred by the protocol, might result in exposure to unknown and potentially serious drug interactions. In turn, the resulting problems might be misdiagnosed if the doctors do not know which drugs are being taken.

Once someone is enrolled in a trial, hopefully all will go well and information will be derived that shows benefit. Volunteers should feel confident that, should more questions arise, there are resources and people to turn to for help. As mentioned above, participants should know whom in the study team to call if there are questions or problems, but Newman strongly advises keeping one's own doctor posted as well. Sometimes, as in the case of Senechek's patient, the best option may be to withdraw from the trial.

While instances of studies putting participants in serious danger are relatively rare, they do occur. One of the most infamous AIDS studies of the eighties involved a drug called suramin, which proved to be dangerously toxic. The study was halted only after a number of participants had died, and several accounts have suggested that the decision to stop the trial came far too late. Some of the participants who had shared information with each other informally and decided to quit the study prematurely may well have saved their lives by doing so.

It can be highly stressful when something in the trial seems to be going wrong. Sometimes "you feel isolated and out on your own," Getty observes. "You call in with a nasty side effect that you've never experienced before, you do not know what it is, and you get an answering service. Then you're put on hold and told a nurse will be paged. This person may or may not call back in the next couple of hours, but usually the nurse will return the call, diagnose your side effect over the phone, and tell you whether or not you're okay."

Sometimes it may not be known if a problem a participant may experience is related to the study drug. Occasionally, Getty complains, he has seen reluctance on the part of researchers to acknowledge that a drug is causing problems. In such cases, communication, not only with the study personnel but also with one's own doctor, can be helpful. Talking to fellow volunteers is also an option, but Getty warns that fellow patients may not be a source of reliable guidance and "can give you a lot of bad information really fast." Ultimately, "you have to decide when to stop" participating in a study, and the fact that a treatment is experimental means your decision will be based on imperfect information. Again, dropping out at any time is an absolute right.

Despite all the potential pitfalls and sources of worry, Getty and Sharp each make a convincing case that they are alive today because of the trials they participated in, not to mention the other studies that evaluated the drugs that have helped them stay alive. Sharp hopes that people with HIV will continue to volunteer, and worries about what he sees as declining enthusiasm for participation in research. "It concerns me that we will not have a mechanism to look at new agents," he says, "because we clearly do not have a cure."

A Resource Guide

Treatment newsletters, such as BETA (www.sfaf.org/beta) and AIDS Treatment News (1-800-TREAT-1-2, or www.aids.org/immunet/atn.nsf/page) frequently carry information about clinical trials and about new drugs and vaccines entering testing. The U.S. Public Health Service runs the AIDS Clinical Trials Information Service (ACTIS), toll-free from the U.S. and Canada at 1-800-TRIALS-A. From outside the U.S. and Canada call 301-519-0459. Trained health specialists, including bilingual English/Spanish specialists, are available from 9:00 a.m. to 7:00 p.m. Eastern Time to answer questions about the studies listed. ACTIS also has a website (www.actis.org).

For a detailed listing of all the HIV/AIDS clinical trials currently open in California, contact the Community Consortium at 415-476-5777 or 1-800-492-5777, or visit hivinsite.ucsf.edu/tsearch for their Trials Search Guide.

Besides information about trials currently enrolling, the ACTIS hotline staff can also provide written fact sheets, including ACTIS's "What is an AIDS Clinical Trial?" and "AIDS: Finding Better Treatments With Your Help," from the National Institute of Allergy and Infectious Diseases (NIAID). These and many other informative documents can also be accessed via a number of websites. Two sites with particularly extensive collections are AEGIS (www.aegis.com) and The Body (www.thebody.com). Both sites have search features that make it reasonably easy to find material on a given topic. AEGIS's "Clinical Trials Knowledgebase" is a concentrated source of information that includes an introduction to clinical trials and study listings by category, location, and disease or condition, as well as links to other Internet resources. This can be found at www.aegis.com/pubs/trials. The Body's main block of trials information, with a number of useful articles, is located at www.thebody.com/treat/clintri.html.

The National Library of Medicine (NLM) offers online computer access to information on AIDS clinical trials as well as other HIV/AIDS research information free of charge. Call the NLM at 1-800-638-8480. NLM information can also be accessed on the Web at www.nlm.nih.gov or through the ACTIS website.

For an extensive, somewhat technical discussion of the structures in place to protect trial subjects and changes that might be needed, see "Updating Protections for Human Subjects Involved in Research" by Jonathan Moreno and colleagues in the Journal of the American Medical Association 280: 1951-58. December 9, 1998. For an analysis of some of the reasons AIDS trials have difficulty attracting volunteers, including trial design issues and restrictions on publicity for trials, see "AIDS Clinical Trials--Why They Have Recruiting Problems," by Bruce Mirken in AIDS Treatment News 217: 1-4. February 17, 1995.