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This section provides answers to many of the questions that people with HIV often ask about clinical trials and their participation in them. It is meant to help you decide whether or not to take part in a particular study, and to help you in discussions with the appropriate healthcare providers before and during a trial. A
glossary of some of the words and phrases used in this section is also available.
Acknowledgments
Tibotec would like to thank
NAM for permission to use the text of this web section.
A clinical trial is a research study used to assess the benefits and risks of a new treatment. It is now widely agreed that a properly conducted clinical trial is the only way to prove that a treatment is effective.
Any new treatment, no matter how promising it appears to be in laboratory tests, has to go through a series of clinical trials in people (healthy volunteers and patients) before its efficacy and safety (usefulness) can really be known.
What sorts of trials are carried out in HIV infection?
Clinical trials for people with HIV are currently testing treatments in five broad categories, at all stages of HIV disease. Some new trials are testing combinations of these approaches:
- Treatments intended to attack HIV at different stages of its lifecycle in order to stop or delay it from damaging the immune system, such as protease inhibitors and/or reverse transcriptase inhibitors, in combination with other antiretroviral drugs.
- Treatments intended to improve the immune system (immunomodulators) such as interleukin 2
- Treatments for the various opportunistic infections, such as oro-pharyngeal candidiasis or CMV-related eye disease (retinitis).
- Preventive treatments (prophylaxis) to prevent opportunistic infections from occurring in the first place, or to stop recurrences.
- Vaccines intended to stimulate an immune response to HIV or other infections.
What types of trial might I be asked to join?
Clinical trials begin only after preliminary studies in the laboratory and with animals. It must have been shown that the drug is safe enough to be taken by people. Clinical trials in people are usually conducted in three steps or phases:
Phase I
Phase I trials test the treatment in only a few people (usually healthy volunteers who are not HIV-positive or those with HIV who are not on other medications) to learn whether it is safe to take, and to find the maximum safe dose. If you enrol in a phase I trial you may have to spend some time in hospital for close monitoring of drug levels in your blood. There are usually no direct health benefits from participating in a Phase I trial.
Phase II
Phase II trials are the first trials that test the treatment in HIV-positive people. These studies typically want to:
- determine whether the drug is effective against HIV (changes in viral load and CD4 count)
- collect the first data on how safe the drug is
- find the most appropriate dose (which balances effectiveness with safety)
If you enrol in a Phase II study you will need to attend the clinic on a regular basis for blood tests and other monitoring. Phase II studies can last from 7 days to 2 years with most lasting 48 weeks. These trials may compare the new treatment with a placebo (an inactive pill).
If the results of phase II trials show the treatment is either not sufficiently active, or if there are too many side effects, no more trials will take place.
Phase III
Phase III trials test the treatment in a larger group of people, often at many different clinics or hospitals. Usually the drug is given in a dose that has been found to be safe enough for most people in Phase I and II trials, and is thought to be active against the disease. These trials compare the new treatment either with a treatment already in use or, occasionally, with a placebo.
Phase III trials usually last for at least twelve months, and also require a commitment to regular clinic attendance.
The different methods of comparing treatments
The treatment being tested may be an entirely new drug added to existing combinations. Or it could be a new way of using existing drugs, such as comparing once-daily dosing versus twice-daily dosing.
Randomisation
This is an essential feature of almost all clinical trials. Everyone who joins the trial will be assigned to one of the treatment groups at random (by chance), usually by computer. This is the best way to make sure that people in different treatment groups of the trial are broadly similar, so that reliable comparisons can be made between the effects of the treatments used in the different trial arms.
Blinded studies
In some trials, neither the researchers nor the participants are supposed to know who is getting the drug and who is getting the standard treatment or no treatment. (The medications are all 'packaged' to look the same.) This is called double blinding (because both researcher and participant are said to be 'blind' to who is receiving what). When only the participants do not know which treatments they are receiving, but the researchers do, then the clinical trial is known as single blind.
The purpose of blinding is to make sure that nobody's expectations affect the results of the trial. A doctor who knows which patients were getting a particular treatment might unconsciously assess or treat them in a different way. Similarly, participants who know their treatment might describe their symptoms differently, or they might choose to stop their trial participation.
Comparison trial
The most common type of clinical trial is a comparison trial. This is a trial in which one group of people who receive a new treatment is compared with another group of people who receive an existing or standard therapy. When there is a recognised standard treatment for a particular condition, then trials will be designed to compare an experimental drug with that standard treatment. In this case it would be unethical to give some trial participants no treatment rather than the standard treatment.
Placebo-controlled trials
Where no standard treatment exists for a disease, or when the drug is studied over a short period of time a trial may compare a new treatment with a dummy drug called a placebo. None of the participants will know whether they are receiving the new drug or the placebo.
Dose comparison trial
Other comparison trials may simply compare different doses of the same drug, or will compare dosing once a day or twice a day. Such trials may or may not be blinded.
Open label or uncontrolled studies
Trials in which treatment allocation is not blinded are also called 'open label'. This means that everyone in the trial, and their doctors, know exactly which treatments they are taking. Some studies will evaluate the effectiveness and safety of a new drug without a control group. This means that everyone who enters the study receives the study medication.
The preparation for a trial
The detailed plan for a trial is called a protocol. It lays down procedures for how the treatment will be given, who is eligible to take part, the timetable for tests and visits for participants, the length of the study, how the results will be assessed and so on.
The protocol is written by a group of doctors or other researchers or by a pharmaceutical company. First, the trial planners will examine previous research on a particular experimental treatment. They then work out the remaining unanswered questions, and design a new trial to try to find out the answers.
Before a study can begin, an ethics committee (in some countries called 'Institutional Review Board') responsible for the clinic(s) that want(s) to run the trial must approve the protocol. The members of the ethics committee may vary, but usually include doctors, nurses, at least one layperson and often a lawyer or chaplain. They are responsible for protecting the rights and interests of the people in the trial, and work independently of those running or financing the trial.
It is very important that any clinical trial should be run with the approval of an ethics committee. Such an approval is a good indication that a trial is ethically sound, even though the committee does not monitor the day-to-day running of the trial.
Recruiting participants
The next step is to recruit participants and start the trial. The more quickly participants are recruited to the trial, the sooner it can be completed and the treatment's benefits and risks can be assessed. The difference between the effect of a new drug and another treatment could be small. The drug may have to be tested in a large number of people to get a clear picture of whether it is better, as good as or worse than other treatments that are currently available.
So, a clinical trial may be seen as a partnership between researchers and people living with HIV. Researchers need people to join their trials so that they can improve medical knowledge about HIV infection. People with HIV may want to help this research, but will also want to make sure that their individual interests are being looked after in the trial.
Who can join a trial?
Each clinical trial has its own rules about who can and who cannot take part. These are known as inclusion and exclusion criteria, or eligibility criteria.
The inclusion criteria spell out the characteristics that will allow a person into the study. This is to make sure that the people in the trial are similar enough so that it will be clear which groups of people might benefit most from the new treatment. Trials of new treatments are usually run in several different groups of people at once in order to build up a bigger picture of the way drugs should be used best.
For example, a particular trial might aim to test the effect of a drug for people who are at a particular stage of HIV disease. In this case a typical inclusion criterion might state that participants in a trial have to have a certain range of CD4 (T-cell) cell count or viral load.
The exclusion criteria are intended to protect the trial participants. For example, you may be excluded from a trial if there is a risk of a dangerous interaction between the trial drug and other treatments that you use. A common exclusion criterion forbids trial participants from taking other drugs at the same time that are similar to the one being studied. For example, people in a trial of an anti-fungal drug may not be allowed to take other anti-fungal drugs while they are on the trial.
Trials sometimes exclude whole groups of people. Most trials exclude pregnant women, because of a fear that the treatment might harm the unborn baby. They also exclude women who are breastfeeding because the drug might be passed onto the child through breast milk. Most trials insist that women are using contraception.
Please note that, although there may be additional restrictions (such as mentioned above) it is vital that women participate in clinical trials, as to find out how the drug reacts in a female body.
The right time to join a trial
There is no right or wrong time to join a trial. People join trials at different times and for different reasons. Some people are not able to join trials because of particular inclusion and exclusion criteria. Some people choose never to join a trial, and there is nothing wrong with saying no. It is something that is best decided in close consultation with your doctor or nurse.
If you are ill and a doctor recommends an experimental drug as the best chance of treatment or offers a new drug as part of a comparative trial, you may have to decide whether or not to take part in the trial at quite short notice. But otherwise, it is worth taking plenty of time to think carefully about your treatment options before deciding whether joining a trial is the best option for you.
Informed consent
Informed consent means that before you can join a trial, the researchers must fully explain the study to you and obtain your agreement to take part. The researchers must explain a number of important things about the trial, such as its purpose, the treatment that will be tested, the number of clinic visits, possible benefits and harms, and so on.
A Patient Information Sheet will also be provided explaining all these things.
Informed consent takes place after all of the important facts about the trial have been explained, when you say that you understand these facts and you agree to enter the trial. It is meant to show that you have made your decision of your own free will. You are fully entitled to change your mind after you have signed this form.
In the case of children, a parent or guardian has to give consent for them to take part in a trial, although older children should also understand and agree themselves.
How to join a trial
If you hear of or read about a trial that interests you, the first step is to talk to the trial's contact person.
The staff at the trial centre will usually ask you some questions to check that you meet the basic entry requirements for the trial, and you may have a physical examination and a blood test. After the results of all the tests are available, the trial staff will let you know whether or not you are eligible to take part.
During a trial
During a clinical trial you have to follow a timetable of treatment, check-ups and blood tests, to see if the treatment is working. The researchers will keep a careful record of your progress.
You may have to go to the clinic for check-ups as rarely as once every six months or as often as five times a week. In some trials these check-ups may be included in your usual appointments. Usually you can take the trial drug at home, but a few trials require you to stay in hospital.
You may have to make some changes to your everyday life. These may include avoiding certain foods, over-the-counter medicines or some homeopathic drugs because they might interfere with the trial drug's action. You may also be required to take the treatment before, with or after meals.
There may also be interactions with alcohol and tobacco, and with recreational drugs such as Ecstasy.
You may also be asked to keep a list of any side effects you notice from the treatment and/or a record of your daily activities, possibly including what you eat.
Reasons for and against joining a trial
Reasons to join a trial
- Access to new drugs
- Because you can't decide what to take
- More frequent monitoring
- You will see the same doctor or nurse each time
- Access to the most advanced tests e.g. ultrasensitive viral load, resistance tests
- In order to benefit others
Reasons not to join a trial
- Because you know what treatment you want
- You don't want to get a placebo
- Too many hospital visits
- You can't stick to the pill-taking timetable
- Anxieties about unknown side-effects
- You are pregnant, or want to be, or don't want to use the required contraception l methods
Questions to ask if you are thinking of joining a clinical trial
How often will I have to visit the clinic?
Some trials will require frequent clinic visits, especially during the first few weeks. It is essential for the smooth running of the trial and the accuracy of the trial results that you are able to attend on the days and at the times you are asked to. Make sure that the schedule for clinic visits is explained to you, and if you think it isn't going to be manageable, explain this to your doctor or the trial nurse.
Some clinics or trials are able to offer financial help with childcare and transport costs. Ask whether these are available for the trial you are thinking of joining.
What will happen at these visits?
Trial monitoring visits will normally include taking blood for viral load tests, CD4 counts and other tests intended to monitor the effectiveness and safety of your treatment. You will also see your doctor, and have the opportunity to report any side effects or problems you are having with taking the medicine. It is especially important to report problems of this sort, because the information you can provide during the trial will help people who take the drug in the future.
Occasionally, a study may require a test such as a bronchoscopy or endoscopy (insertion of an optical tube down the throat and into the lungs or digestive tract), or a lymph tissue biopsy (removal of a microscopic portion of tissue from the lymph nodes or tonsils), or a liver biopsy (removal of a microscopic portion of liver tissue) or a lumbar puncture (insertion of a needle into the spine to withdraw spinal fluid). These investigations are rare, but ask at the beginning of the study whether any special procedures will have to be carried out at any time.
When will I get the results of blood tests?
Some trial protocols will permit you to receive the results of viral load tests and CD4 counts in 'real time' - within a few days or weeks of the test. This will allow you to discuss options with your doctor if your viral load appears to be increasing, or has not been suppressed satisfactorily.
However, other studies will not provide this information to patients. It will be left up to your doctor to decide when you should come off the trial medication if you show signs of a poor response to your current treatment. It's up to you to decide whether you want to take part in this kind of trial.
What other medications or drugs can I take while on this trial?
The trial protocol will usually specify certain drugs that should not be taken in case they could confuse the outcomes of the trial. To be ethical, trials must allow participants to receive the current standard of care. However, many drugs used in HIV therapy have interactions with other drugs. In the case of experimental drugs, ask what is already known about interactions. Ask for a full list of the medicines, including over-the-counter medicines or homeopathic remedies that should be avoided.
Many investigators may also choose to exclude current injecting drug users. This is because there is a risk that opiates, amphetamines, barbiturates, cocaine and/or impurities in injectable forms of these drugs may lead to harmful interactions with the study medication.
Are there any restrictions relating to birth control or pregnancy?
Many trials require women who could become pregnant to be using contraception. However, some may not allow the use of the contraceptive pill in case there is an interaction with the study medication. Find out what sort of contraception is allowed or required. Most trials exclude pregnant and breastfeeding women. Find out what you would have to do if you thought that you had become pregnant while in the trial, and what is known about the potential effects of the study medication on the unborn child.
What happens if my condition worsens?
Some trials require you to leave the trial if your condition worsens beyond a pre-defined point. For example, if your viral load does not fall below the limit of detection after a period of time on the drug, or if your viral load rises above the limit of detection after being undetectable, you may have to leave the trial. Some trials guarantee that people who have been receiving a placebo will be switched over to receive the active trial drug if their condition deteriorates. Check what the procedure would be in your study.
How long will the study last?
In the protocol, the researchers usually give an estimate of how long the trial will last. While some trials last only a few weeks, others can go on for years. In many large trials, a special group of independent experts and lay people, called a Data and Safety Monitoring Board, checks regularly on the results of the trial while it is taking place. If they find that one group of patients is doing much better than the other, they can recommend that the trial is stopped earlier than planned so that the better treatment can be offered to all the participants. They can also recommend that a trial should be stopped if many trial participants develop serious side effects.
Some trials collect information on the participants' health even after the trial has stopped. If the results are favourable, some trials will offer a supply of the drug to all participants in the study until it becomes available through other access programmes or is licensed for doctors to prescribe.
How will this trial affect my future options?
One of the most important things that may be studied in a trial is how resistance to the trial drug develops. Developing drug resistance is one of the risks of participating in a clinical trial, but it is a potential risk of many forms of antiretroviral treatment. In a clinical trial, clear safeguards should be built into the design of the trial to minimise the risk that you will develop resistance. Conversely, some new treatments may actually work to preserve future options.
Participation in a trial of one drug can also affect your opportunity to join future trials, whether or not you develop resistance to the drug. This is because it is often preferable to test new drugs in people who have absolutely no risk of cross-resistance, in order to get clear results. So if you have previously taken a protease inhibitor, you may be excluded from a future protease inhibitor trial because the researchers want to test the drug in protease inhibitor 'naive' people - those people who have never taken one.
Will I be informed of the trial's results when it ends?
Some researchers and drug companies have not been good at communicating trial results to the people who took part. Many people may find it unacceptable that they are not informed of the practical outcome of their time in the trial, or only stumble across the results by chance in (often distorted) newspaper accounts. After you have finished your participation to the trial, it may take a while before the trial's results become available. Ask when and how the researchers will inform you about the trial results.
If, for any reason, you don't approve of the trial design, it is important to tell the researchers. For instance, if you believe that joining the trial is the only way of getting an experimental treatment, you may decide that your interests are best served by joining the trial even though you are unable or unwilling to follow the rules. However, the researchers may be able to suggest other options if you are honest with them.
How will other drugs taken during the trial be chosen?
An increasing number of trials are aimed at people who already have the experience of previous anti-HIV treatment, and these people may have resistance to some drugs. Unless the trial is specifically designed to recruit only those people who have taken particular drugs in the past, you will be offered the opportunity to choose the drugs you take alongside the trial drug in the way now considered to be the standard of care - by resistance testing.
If the trial does not offer resistance testing and your clinic does not routinely use resistance testing to select new drugs when you change treatment, the study is not offering the preferred standard of care.
Thinking it over
Do not rush into a decision about joining a trial. Take time to consider all of your options and all the pros and cons. Make sure that you have had time to consider how the trial might affect you. Make sure you have had a chance to discuss all your questions or concerns with the doctor and/or study team.
It is sensible to adopt a sceptical attitude if you are ever told that a clinical trial has no possible drawbacks or hazards: this is rarely true of any treatment. After all, if we knew that a drug was completely safe and effective, there would not be any need for the trial.
There should be written information provided which you can take away and read at leisure. If a trial is already under way, ask if it is possible to meet or talk to someone who has already taken the drug.
There is nothing wrong in saying 'no' or asking for more time to think about your decision.
It may be helpful to think about how you reached a decision on an important or complicated question in the past. Perhaps you could talk through the issues with a friend, who may help you to clarify your own views. You might also find it useful to contact one of the many excellent patient and/or community groups in your area.
Rights and responsibilities
If you join a trial, you have certain responsibilities to the trial researchers. The researchers should also respect certain rights that you have.
Your rights when you join a trial
First and foremost, no one should force or pressure you into entering a trial. It is a choice that you alone can make after you have received and understood all the facts about the study. You have the right to get understandable answers to any questions that you may have before you agree to enrol.
Once you have entered the trial you have the right to withdraw from it at any time without this affecting the regular medical care you receive. You do not have to give any reason.
Feel free to ask about the results of any tests that you have to take during the trial. You will probably want to keep track of your progress in the trial to help you decide whether to continue in the trial or not. But bear in mind that many trials are double-blinded, meaning that neither you nor your doctor knows which arm of the trial you are in. So, even your doctor may not be told the results of some of the tests performed upon you.
Finally, you should always be able to contact someone after normal clinic hours with any important concerns or urgent questions you may have about the treatment, its side effects or any other symptoms. When you decide to join a clinical trial, you will receive a card with these contact details.
The responsibilities of joining a trial
The researchers have set up the trial to answer specific questions. Nobody gains if the trial is unable to answer those questions. So it is important that you follow the rules of the trial as far as possible, and tell your doctor if you cannot follow any of them. For example, if you find it difficult or forget to take trial medications, it is best to let the researchers know so that they can interpret the trial results properly.
Even though all the tests and restrictions might require a lot of your effort, they are designed to protect you against unknown side effects, and to get reliable information about the treatment. Making an effort to follow the rules of the trial helps everyone.
It may be helpful to ask the researchers to spell out your responsibilities at the start of the trial. For example, you may find that you have to miss a clinic visit, or you might forget to take the trial drug. Check whether these may affect your rights to continue in the trial.
For safety reasons, it is worth taking some time to tell the researchers about any relevant aspects of your medical history, such as previous drug allergies or any other treatments you are currently taking. You may also be asked if you are taking any recreational drugs.
It is important to tell the researchers about any new symptoms you may experience, even such things as rashes and headaches. These may seem unimportant at the time, or you may suspect that you are on a placebo and that therefore these are not side effects of the drug. However, you may be wrong. It is your responsibility to tell researchers in order to give them the maximum information with which to judge the harms and benefits of the treatment.
The best protection against serious side effects during a clinical trial is to learn about the symptoms of possible side effects. Promptly notify the investigators whenever there is a change in your health - even if it is only a headache or rash.
Deciding not to join a trial
If you decide not to enter the trial, or if you decide to leave the trial after it begins, you still have the right to the same medical care that any other person receives.
Remember that you are not necessarily saying 'no' to all clinical trials. Make sure that you keep up-to-date about other options and new trials.
Leaving a trial
You and your doctor might decide that you stop a trial treatment if your condition is getting worse and/or the therapy is not helping you. Do not feel bad about leaving trials because of side effects. Information from your participation will help others in the future.
The researchers will usually want to continue to follow your progress after the trial, even if you leave it early. This is in your best interest and helps them to interpret the results of the trial accurately.
Summary
- A clinical trial is a research study used to assess the benefits and risks of a new treatment.
- There are various methods of comparing treatments within trials. Some allocate treatment by chance; some allow participants to know which treatment they are taking whilst others do not; and some allocate some participants to receive a dummy drug rather than the trial drug.
- All trials lay down criteria for who can and cannot join the trial.
- All participants must give their fully informed consent to take part in the trial. Asking questions of your doctor and researchers involved in running the trial is part of the process of giving, and we suggest some relevant questions in this booklet.
- You should not feel pressured into joining a trial. Similarly, don't join a trial if you feel unsure you want to take part. Remember, you are free to leave a trial at any time, if you choose to do so.
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