While the information you're about to read will focus largely on the testing of drugs, please keep in mind that clinical trials may also include scientific research into other arthritis treatments as well as patient care and public education initiatives.
Because - as a top researcher once remarked - 'there's just so much you can learn from a mouse,' the human volunteers who participate in clinical drug trials are medicine's true unsung heroes. They are risk-takers for the best of reasons: improving the quality of life of others.
No drug could possibly be approved for sale without the help of ordinary people willing to be among the first to try an experimental compound. In the final analysis - despite sophisticated computer models, repeated laboratory experiments and extensive animal testing - the only way to be really sure a new drug works safely in humans is to have humans try it. Clinical trials are the carefully designed experiments that allow these tests to happen.
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 arthritis, scientists, doctors, other health care providers, industry and governments must work together. People living with arthritis 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 and other health care providers monitor the progress of people involved in the trial, and pass that information to the researchers. Industry provides the drugs and usually fund the trials. Government 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.
If you have ever thought about volunteering for clinical drug trials, this section contains some background information that will give you some perspective on this exciting aspect of research. The majority of this information is provided here courtesy of the Canadian AIDS Society and its excellent booklet Clinical Trials: What You Need To Know [PDF]. The booklet, and any additional information included here, does not endorse any particular trial or try to persuade people to participate in a clinical trial. It simply 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.
What are Clinical Trials?
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 inflammatory 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 toxicology 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.
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 phase, 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 and 2 trials might study both drug dose and how it works. Phase 2 and 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 arthritis 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, 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 are 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.
Most trials now compare one treatment with another in one of 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. 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 judgement 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 Clinical Trials Test?
Most treatments tested on people living with arthritis fall into some of the following categories:
- drugs that fight inflammation (anti-inflammatories)
- drugs the modify the arthritis (disease modifying anti-rheumatic drugs)
- drugs that fight pain (analgesics)
- corticosteroids
- 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. While many clinical trials in Canada take place in cities that have university teaching hospitals with clinics specializing in arthritis disease, many others involve the participation of community rheumatologists and, sometimes, family doctors from across the country. These site investigators run trials from their offices. In all these cases, the clinical trials are operated according to strict government regulations and guidelines which are enforced by the investigator’s Institutional Review Board or Ethics Review Board.
Deciding to Participate
Where to Start
People living with arthritis who are interested in participating in a clinical trial can talk to their doctors about treatments they are interested in and trials going on in their area.
People who are interested in a treatment available through a trial, can contact their family doctor who can refer them to the site investigator, or they can call the site directly. A telephone interview with the trials nurse or other member of the trials staff will likely provide enough information for them to decide whether they 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 have osteoarthritis of the knee, be 40 to 80 years of age and require anti-inflammatories”.
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 diabetes, or who is pregnant will likely be excluded from a trial. Pregnant women are almost never allowed to enter drug trials in case the drug harms the unborn child. Women of child bearing years are required to use a reliable method of contraception as determined by the study or the investigator.
To determine whether people qualify to participate, researchers use a screening interview. There is no obligation to participate in the trial simply because you’ve attended the screening interview. It can and should be treated as an information gathering session. At the interview, people living with arthritis will be:
- asked detailed questions about their health, their medical history, and the drugs and treatments they use
- given an extensive physical examination, along with lab tests (usually blood tests, sometimes x-rays or other tests).
At the end of the interview, they may be asked if they want to enter the trial or they 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 usually receives 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 their family doctor, a partner, friend or relative. In making the decision, they should consider all the potential benefits and problems or risks:
Benefits
- helping other people living with arthritis 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
- not 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.
Questions to Consider
- What’s the purpose of the clinical trial?
- What kind of medication is involved?
- How will the study affect my daily life?
- Can I continue to take my usual medications?
- Where is the closest clinical trial site?
- How many doctor visits will there be, and how long will they last?
- What kind of procedures are required - blood and urine tests, x-rays?
- What is likely to happen to my symptoms with or without the study drug?
- What are the possible side effects of the study drug?
- What are the other treatment options available for my condition, and what are their risks and benefits?
- Who pays for expenses associated with the clinical trial?
The Informed Consent Process
People who meet the inclusion criteria and who decide to take part in the trial will be asked to give their informed consent.
Giving informed consent means that they:
- understand that the trial is a scientific experiment and there may be risks and dangers to their health
- have been told about the reasons for doing the trial, the drugs they might be given, the number of visits and the kinds of lab tests required
- have been given the information they need to decide whether to take part in the trial.
Anyone who is concerned about any of the requirements of the trial should talk to trial staff about them before giving informed consent. Staff may be able to make some exceptions, or the person may decide not to take part in the trial after all.
When potential participants have all the information about the trial, they 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. The participant should receive a copy of the signed consent form.
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 a person's regular health care or the ability to participate in other trials.
The Role of the Family Doctor
Clinical trial participants have their health monitored at the trial site. However, they 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 Happens When You Enroll
The Stages of Trial Participation
Participants may be required to wait a few days or even weeks before starting to take the trial medication. During this time, investigators observe their health before treatment begins. Participants may also be asked to go through a waiting period when they stop taking a drug or medication before they start taking the trial drug. This is called the washout period, and it allows participants to get rid of all traces of a drug in their bodies.
The treatment period is the length of time participants take the study drug. If a trial is designed to last for 6 months, then the treatment period is 6 months from when the participant starts taking the drug.
The post-treatment period is the length of time participants are followed after the treatment period. Participants may be asked to return to the clinic and check in with the investigator after they complete the trial. The follow-up can be once a month for the first six months or one visit six months after participants finish the trial, depending on the protocol.
It is important for participants and investigators to stay in touch after a trial ends, so participants can report any recurring symptoms or side effects, and investigators can give participants any new information about the drug.
As noted earlier, if any new information about the trial drug becomes available during the trial, the sponsors and the investigators must tell participants.
What are Participants' Responsibilities during the Trial?
Participants' main responsibility is to be sure they 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 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?
The time when people enter and leave trials is often staggered. For example, a person who enters a two-year trial when it first begins, will complete the trial two years later, while someone who enters the same trial after it has been running for a year will take the trial drug for the two years, and will complete the trial after the trial itself has been running for a total of three years. The “two years” describes not the total length of the trial, but the total time that participants will be taking the trial drug. A two-year trial of a drug may take several years to complete, and the time will vary depending on how quickly researchers can get enough people enrolled in the trial.
When participants' time in a trial comes to an end, they will have an exit interview. During this interview, they may be told what drug they were taking (if they didn't already know) - depending on the type of trial and the time they 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.
If a trial ends early because the drug didn't work or was too dangerous, participants will be told.
What does it cost to participate in a trial?
Provincial health insurance and the drug manufacturer typically cover the cost of drugs and lab tests. However, there are other costs involved, such as time off work, transportation costs, babysitting or daycare. If participants need help with childcare or transportation costs, they 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 participants are getting their drug through a hospital or local pharmacy, there may be a dispensing fee.
What if participants get sick during a trial? Participants who become sick while in a trial should let trial staff know as soon as possible. All illness, regardless of its relationship to the trial, should be reported to the study’s investigator. They may be experiencing side effects from the drug or an illness the study drug could make worse.
Participants should keep the informed consent form and trial information package handy. They usually include a 24-hour toll-free number 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.
Can participants take other drugs while in a trial?
While in the trial, participants may not be permitted to take certain medications if:
- the trial medication may interfere with other drugs, making one or more less effective
- the trial medication might cause a reaction that another drug may make worse.
To protect themselves, participants should keep a list of all the medications they take, even over-the-counter drugs like cold tablets, cough syrup or vitamins.
Glossary of Terms
Clinical trial:
An experiment to see how well a new drug works in people and how safe it is.
Comparative trial:
A trial in which experimental drugs are tested against each other or against an approved drug or placebo.
Controlled trials:
Trials in which one group gets the experimental drug and another gets either a placebo or an approved drug therapy. Participants do not usually know which group they are in.
Dose comparison:
A trial that uses different amounts of the same drug. Sometimes different doses are tested against a placebo.
Double-blind:
People in this trial are divided into two or more groups. One group takes the experimental drug, and the other takes the standard therapy or a placebo. Neither the researchers nor the people in the trial know who is taking which drug until the trial is over.
Emergency Drug Release Programme (EDRP):
A participant's doctor may ask the Bureau of Human Prescription Drugs of Health Canada for the release of an experimental drug on an emergency basis, if the drug manufacturer has authorized its release. The programme applies to new drugs not yet marketable and drugs currently used in clinical trials, as well as drugs approved for use in other countries, but not yet in Canada.
Inclusion\Exclusion criteria:
The medical or social reasons why a person may or may not be allowed to enter a trial. For example, most trials do not allow pregnant women to join. Others do not allow people to take certain drugs, and others exclude people with certain illnesses.
Informed consent:
A process in which the risks, benefits, and requirements of a trial are explained to people thinking of joining the trial. Before entering the trial a participant should sign an informed consent form, which should contain in writing the benefits, risks, and basic structure of the trial.
Institutional Review Board:
The U.S. equivalent of a Research Ethics Board. It operates under stricter regulations than REBs.
Open label:
A type of clinical trial in which researchers and participants know who is taking the experimental drug.