Clinical Trials - What You Need to Know
-Canadian AIDS Society and Canadian HIV Trials Network, Second Printing 1999
This information is intended to give people living with HIV, their families and friends - any anyone else who is interested - some basic information about clinical trials. It does not endorse any particular trial or try to persuade people to participate in a clinical trial. It explains the purpose of clinical trials, how they are conducted, how people can join a trial and what they can expect from a trial if they decide to participate.
Clinical trials are carefully designed experiments that allow scientists to test newly developed drugs on a small group of people. They are a logical, structured way to answer questions about how to control HIV, and how to prevent and cure many infections associated with AIDS. Clinical trials are the most effective way for scientists to assess whether the benefits of using a drug outweigh any risks, and if the drug will improve life for people living with HIV.
Researchers have used clinical trials to develop effective treatments for many types of cancer and bacterial infections, and vaccines for many childhood illnesses. Over the last 10 years, clinical research in HIV has led to treatments for many opportunistic infections, and treatments against HIV itself. These treatments help people with HIV live longer, with a better quality of life than was possible ten, five or even two years ago.
Clinical trials are one stage in the whole process of developing a new drug treatment. The entire process - identifying a possible drug treatment, testing it on animals, getting approval for a clinical trial with people, running the trial, analyzing the results, applying for a license and getting approval to use the drug in regular treatment - takes a long time, sometimes many years.
Planning and running a clinical trial involves teamwork. To find effective treatments, people living with HIV, scientists, doctors, drug companies and governments must work together. People living with HIV help ensure researchers are aware of their needs and concerns, and they participate in the trials. Researchers ensure that the trials are of the highest scientific quality, and they analyze the results. Physicians monitor the progress of people involved in the trial, and pass that information to the researchers. Drug companies provide the drugs and usually fund the trials. Governments and other funding bodies may also help pay for the trials, and government regulatory agencies are responsible for reviewing the results of the trials and deciding, based on the scientific evidence, whether to approve the drug for wider use.
People living with HIV have been particularly active in scientific research - more so than groups of people organized around other illnesses. They have worked with researchers, drug companies and governments to ensure that clinical trials reflect their concerns, and that policies and practices are fair and ethical.
What is a Clinical Trial?
A clinical trial is a scientific test of new drugs or treatments on people, designed to find out if new drugs are safe and how well they work.
How do Trials Work?
Before a drug is given to people
When a new drug is developed, it must be carefully tested before it can be given to people. These pre-clinical tests include in vitro studies and animal studies:
- In vitro studies are laboratory experiments to find out if a new drug works on human cells in test tubes. For example, the new drug may be mixed with some healthy cells and some HIV-infected cells to see if it will kill infected cells without damaging healthy ones. In vitro studies are repeated many times to ensure the results are dependable and not just due to chance. If the drug shows promise, researchers then go to the next stage: animal studies.
- In animal studies, the new drug is given to animals to see how it works in a living creature. Some animal studies are toxicity studies designed to find out if a drug is dangerous to the body or to some of its organs or systems. Sometimes drugs can cause illnesses or reactions that don’t show up unless they are used for a long time. Other drugs may be fine for the people taking them but cause birth defects in the next generation. Because animals, such as mice and rats, have short life spans and reproduce quickly, they can be used to study both these problems. Other animals, such as monkeys or chimpanzees, are used because they are more like people or can get the same diseases as people. Testing the drug on them can give scientists a better idea of how it will affect people.
Clinical trials are done to determine the safety and efficacy of a new treatment. They are designed to answer one or more of the following questions.
1. Is it safe?
2. Does it work?
3. Is it safe over a longer period?
4. Does it work in many people over a long period of time?
5. Are there any long term side effects?
Testing new drugs in people
If, after pre-clinical studies, the drug seems to be useful and safe in animals, the drug company asks the federal government for permission to test the drug in people. To get approval for the clinical trial, the company must submit all documents and data on pre-clinical studies as well as a detailed plan or protocol for the trial to the Health Protection Branch (HPB) of Health Canada. If the HPB gives approval, clinical trials can start.
Once approved, a clinical trial goes through four phases:
- in the first phase, researchers give the drug to a small number of people to see what dose is safe.
- In the second, they give a larger number of participants the appropriate dose over a longer period of time to see if the drug is working and whether it has any long-term side effects.
- In the third phase, researchers give the drug to a much larger group of people over several months or years to see whether the drug remains useful or has any side effects that only show up after a longer period of time.
- In the fourth phase, researchers continue to study the drug even after it has been approved in what are called "post-marketing" trials. They can then watch for any side effects or problems that may show up after several years of treatment.
Today, many clinical trials combine phases. For example, Phase 1/2 trials might study both drug dose and how it works, or Phase 2/3 trials might study both how the drug works and how well it works at the same time. Combined phase trials are more common with drugs that are already used to treat other illnesses and are being tested as an HIV therapy. They have the advantage of moving more quickly than single phase trials.
Measuring the Effects of a New Drug
Monitoring the Trial
At each phase of the clinical trial, the drug must be reassessed and approved by the Bureau of Human Prescription Drugs before it can go on to the next stage of testing. Once a drug has been tested successfully in the lab, in animals and in people in the first three phases, the drug manufacturer applies to the Health Protection Branch for formal approval to market or sell the drug. The company must provide all the results from the clinical trials, and the Health Protection Branch reviews the information and decides, based on the scientific evidence, whether to permit the sale of the new drug.
Federal government approval doesn’t necessarily mean the drug is effective or safe for all people at all times. It only means that it has proven useful in enough people that it’s worth trying, and that its known side effects are considered "satisfactory" or not dangerous.
Types of Clinical Trials
All clinical trials compare a new drug with something else to find out which is better and safer. In the early days of the HIV epidemic, many trials compared a drug with a placebo. A placebo is something that looks, smells and tastes like the drug, but has no drug in it. In these trials, one group of people is given the drug, another group the placebo, and both groups are studied to see their reactions. Placebo trials are a quick, accurate way to assess whether the drug is better than doing nothing. However, in Canada, we consider it unethical to give a placebo to people who are participating in a trial if a standard therapy is available. For this reason, placebo-controlled trials are rarely used in HIV.
Most trials are controlled, comparison trials which compare one treatment with another in the following ways:
- One type of trial compares a new treatment with a commonly used treatment. In these trials, one group receives the commonly used treatment, another group the new treatment. Scientists compare the two to see which works better.
- Another type of trial compares a new treatment combined with commonly used treatments to the commonly used treatments alone. Both groups receive commonly used treatments, but one group also receives the new treatment. Researchers then assess whether adding the new treatment has a positive effect on health and/or quality of life.
- A third type of trial compares the use of a new drug at different doses (dose comparison). Researchers then assess which dose works best and has the fewest side effects.
Other measures researchers use to ensure accurate results are called controls. These are the specific rules that researchers and participants must follow to reduce any "bias" that could affect the results. For example, personal beliefs, interests or emotions can influence or "bias" someone’s judgment and affect the results of a trial. Controls include:
- Randomized, controlled trials, which divide participants randomly into the two test groups using a computer. This helps remove any bias from deciding which participants receive the new drug or treatment.
- Double-blind, controlled trials, which ensure that neither the participants nor the doctors know who has received which treatment. The trial remains blinded until the last person to volunteer has completed the trial.
What Treatments Do HIV Trials Test?
Most treatments tested on people living with HIV fall into six categories:
- drugs that fight the virus, called antiretrovirals or anti-HIVs
- treatments that prevent or treat HIV-related illnesses (opportunistic infections such as thrush or pneumocystic carinii pneumonia (PCP))
- drugs that treat cancers
- treatments that reinforce the immune system, known as immunostimulators or immunomodulators
- vaccines that could prevent or cure HIV infection
- gene therapies
Who conducts Clinical Trials?
Clinical trials in Canada are usually sponsored (designed and paid for) by the company that developed the new drug. The principal investigator is the researcher supervising the trial, usually a doctor with a lot of experience running clinical trials. The trial may take place at several locations across the country. Each of these locations is called a trial site, and each site has a doctor in charge of the trial, called a site investigator. Most HIV-related clinical trials in Canada take place in cities that have university teaching hospitals with clinics specializing in HIV disease. Sometimes family doctors will be investigators and run trials from their offices.
How do researchers assess the results?
Investigators use certain tests and measurements, often called surrogate markers, to assess the effect a trial drug has on a participants’ health. For example, researchers may take blood or tissue samples and measure the amount of virus present (i.e. a viral load test) before participants take the trial drug, while they are taking the drug, and after. If your viral load is high, it means the virus is replicating quickly in your body. If your viral load is low it means your body itself or your treatment is keeping the virus in check. Another commonly used surrogate marker is the CD4+ count, the blood test that measure the white blood cells that regulate the immune system. A low or dropping CD4+ count is a sign that HIV disease is progressing.
Throughout the clinical trial, researchers will test for these and other surrogate markers, hoping to see signs that the drug is having a positive effect on health.
Participating in Clinical Trials
Where to Start
If you are living with HIV and interested in participating in a clinical trial, talk to your doctors or local AIDS organization about treatments in which you are interested and trials going on in your area. You can also get information from:
- the Canadian HIV Trials Network (CTN), a federally funded organization whose mandate is to develop treatments, vaccines, and a cure for HIV disease and AIDS through the conduct of scientifically sound and ethical clinical trials. The CTN publishes a bimonthly newsletter, including a directory of enrolling clinical trials (compiled in conjunction with CATIE), and operates an information line at 1-800-661-4664. The CTN will provide phone numbers of the trial site nearest you.
- The Treatment Information Network is a national service operated by the Community AIDS Treatment Information Exchange (CATIE), at 1-800-263-1638. CATIE offers mainly treatment information, helping people living with HIV/AIDS and their caregivers make informed healthcare decisions.
If you find a particular trial in which you are interested, you can contact your family doctor who can refer you to the site investigator, or you can call the site directly. A telephone interview with the trial nurse or other member of the trial staff will likely provide enough information for you to decide whether you want to participate. Anyone who is interested can make an appointment for a screening interview.
The Screening Interview
To qualify for the trial, participants must be assessed against strict requirements, called inclusion and exclusion criteria.
Inclusion criteria make sure that a fairly similar group of people take part in a trial and allow researchers to make reliable comparisons about the way the drug works. For example, to be included in a trial, participants: "must be HIV+" and "must have a CD4+ (T4) cell count between 100 and 300.
Exclusion criteria protect people who might be harmed by the study drug. For example, anyone who is being treated for an active illness, such as PCP, or who is pregnant will likely be excluded from a trial. Until recently, pregnant women have almost never been allowed to enter drug trials in case the drug harms the foetus. However, recent guidelines in the United States and Canada have made it increasingly acceptable to include pregnant women in particular circumstances.
To determine whether people qualify to participate, researchers use a screening interview. At the interview, you will be:
- asked detailed questions about your health, your medical history, and the drugs and treatments you use; and
- given an extensive physical examination, along with lab tests (usually blood tests, sometimes X-rays or other tests).
At the end of the interview, you may be asked If you want to enter the trial or you may be asked to return to the clinic for a second interview, when the lab test results are available.
Making a Decision
Anyone considering taking part in a trial should obtain an information package with all the details, and should also discuss with trial staff what the trial will mean to them and their lifestyle. People invited to participate in a trial should take the time needed to make this decision. They may want to talk it over with a partner, friend, relative or local AIDS group. In making the decision, they should consider all the potential benefits and problems or risks:
Benefits
- helping other people living with HIV and AIDS by being part of a process that develops new treatments
- being one of the first to benefit if an experimental therapy turns out to be effective
- receiving the regular health monitoring that is part of the trial, which may be beneficial
Risks
- having no guarantee of a personal benefit from the trial
- having side effects that could be dangerous or make health worse
- having to stop taking other medications that are working well
- not being eligible for other trials
- now knowing who is receiving the experimental drug
- having to make changes in lifestyle, such as taking medication at very regular intervals, or not eating certain foods
- having to go into hospital
Trial staff should explain all the known benefits and risks.
The Informed Consent Process
If you meet the entry criteria and decide to take part in the trial, you will be asked to give your informed consent.
Giving informed consent means that you:
- understand that the trial is a scientific experiment and there may be risks and dangers to your health
- have been told about the reasons for doing the trial, the drugs you might be given, the number of visits and the kinds of lab tests required.
- Have been given the information you need to decide whether to take part in the trial.
When you have all the information about the trial, you are asked to sign an informed consent form, which should explain the trial and the possible risks or dangers in plain language. Informed consent forms usually require the participant’s signature, the signature of a witness and the signature of the principal or site investigator.
Once you sign the Informed Consent Form, you are considered enrolled in the trial.
However, informed consent is an ongoing process. The investigators have a responsibility to give participants any new information about the drug they are taking. Participants have the right to leave a clinical trial at any time. Leaving a trial will not affect your regular health care or your ability to participate in other trials for which you meet the entry criteria.
The Role of The Family Doctor
Clinical trial participants have their health monitored at the trial site. However, participants should also continue to see their own doctors - who continue to be responsible for their overall health - for regular check-ups and lab tests. It is not ethical for the trial doctors to take over participants’ general medical care. To avoid having the same tests repeated in both places, family doctors and site investigators usually work out a way to share test results.
When family doctors are also trial investigators, they should ask another doctor to go over the trial protocol and informed consent with their patients. In addition, they may recommend that any of their patients who are participating in the trial see another doctor for their regular care during the trial. This is one way to ensure that the doctors’ interest in enrolling volunteers for the trial does not conflict with the obligation to provide the best possible patient care.
What are Your Responsibilities during the Trial?
Your main responsibility is to be sure you understand the rules of the trial and are realistic about their ability to follow them. Participants who won’t be able to keep appointments or follow the schedule should talk to the trial staff. There may be ways to work around people’s schedules. Participants who do not follow the trial rules can be withdrawn.
Can participants leave a trial?
Participants can leave a trial at any time, for any reason.
What happens when the trial ends?
When your time in a trial comes to an end, you will be asked to participate in an exit interview. During this interview, you may be told what drug you were taking (if you didn’t already know) - depending on the type of trial and the time you exit. Since the code in double blind trials is not broken until everyone has completed the trial, participants in those trials may not find out what treatment they were getting until some time after they finished the trial.
You should expect to receive the results of the trial when it is finished. If information about how these results will be given to you is not in the informed consent form, ask the study staff. Keep in mind that because enrollment is staggered, a two year trial may take several years to reach conclusion because the last person enrolled must have been on the study for a full two years.
What does it cost to participate in a trial?
Provincial health insurance and drug manufacturer typically cover the cost of drugs and lab tests. However, there may be other costs involved, such as time off work, transportation costs, baby-sitting or daycare. If you need help with childcare or transportation costs, you should ask the trial staff. In some cases, funds are available to cover these costs, and trial organizers should explain what costs will be reimbursed, how, and when.
It is illegal for anyone to sell a drug that hasn’t been approved by the Health Protection Branch of Health Canada. However, if trial participants receive their trial drug through a hospital or local pharmacy, there may be a dispensing fee.
What if you get sick during a trial?
If you become sick while in a trial, you should let trial staff know as soon as possible. You may be experiencing side effects from the drug or an illness the study drug could make worse.
You should keep the informed consent form and trial information package handy. A 24 hour toll free number is usually included to call for advice if there are problems with the trial medication. Because the drugs being tested are experimental, doctors in emergency rooms may not be able to help participants who become ill. However, if you are very ill, go to Emergency but take your Informed Consent Form with you so the emergency doctors can contact your trial doctor.
Can you take other drugs while in a trial?
While in the trial, you may not be permitted to take certain medications if:
- the trial medication interferes with other drugs, making one or more less effective;
- the trial medication causes a reaction that another drug may make worse.
To protect yourself, you should keep a list of all the medications you take, even over-the-counter drugs like cold tablets or cough syrup. Also be aware that the potential for interactions with street drug (e.g. heroin, cocaine, ecstasy, etc.) is unknown for most experimental HIV drugs.
Where to Find Help
The following list includes organizations or programs engaged in HIV treatment advocacy and/or who provide information on HIV treatments, clinical trials, and drug access.
ADVOCACY
AIDS Action Now!
321-517 College Street
Toronto, ON, M6G 1A8
Tel.:(416)928-2206
Canadian AIDS Society (CAS)
900-130 Albert Street
Ottawa, ON, K1P 5G4
Tel:(613)230-3580
casinfo@cdnaids.ca
www.cdnaids.ca
National coalition of over 100 community-based AIDS organizations across Canada. A list of these organizations can be found on their web site or by contacting CAS by phone or fax.
Canadian Treatment Advocates Council (CTAC)
Box 116, Station F
Toronto, ON, M4Y 2L4
Tel.:(416)422-2179
ctac@sympatico.ca
Voices of Positive Women
P.O. Box 471, Station C
Toronto, ON, M6J 3P5
Tel.:(416)324-8703
vopw@idirect.com
web home.idirect.com/~vopw
TREATMENT/CLINICAL TRIAL INFORMATION
Canadian HIV Trials Network
National Office
620-1081 Burrard Street
Vancouver, BC, V6Z 1Y6
Tel.:1-800-661-4664 or (604)806-8327
ctn@hivnet.ubc.ca www.hivnet.ubc.ca/ctn.html
Community AIDS Treatment Information Exchange (CATIE), The Treatment Information Network
420-517 College Street
Toronto, ON, M6G 4A2
Tel:1-800-263-1638 or (416)944-1916
info@catie.ca www.catie.ca
Local CAS Member Groups
Also, many of CAS’ member organizations have locally-based treatment information programs. A list of these organizations can be found on their web site or by contacting CAS by phone.
DRUG ACCESS INFORMATION
Special Access Programme
Bureau of Prescription Drugs
Tower B, Place Vanier
355 River Road
Ottawa, ON, K1A 1B8
Tel:(613)941-2108
REFERENCE
American Foundation for AIDS Research
120 Wall Street
Thirteenth Floor
New York, NY 10005
(Publishes HIV/AIDS Experimental Treatment Directory, as well as a directory of all clinical trials in the United States)
Tel:(212)806-1600
txdir@amfar.org
www.amfar.org
Canadian HIV/AIDS Clearinghouse
1565 Carling Avenue
Suite 400
Ottawa, ON, K1Z 8R1
Tel:(613)725-3434
aidssida@cpha.ca www.cpha.ca
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