Whether positive or negative, the results feed a growing body of medical knowledge that helps improve the management of people with cancer.
Types of clinical trial
Medical research investigating the effectiveness and/or safety of a new therapy or procedure in patients is known as a clinical trial or treatment trial. Other types of trials include: - Screening trial – to check for disease when there are no symptoms
- Genetic trial – to study the genetic factors that may influence the development of a disease or the response to treatment
- Supportive care trial – to study treatments to prevent, control, or relieve complications and side effects of a disease, and to improve patients' comfort and quality of life
- Prevention trial – to study methods of preventing a disease
- Diagnostic trial – to evaluate methods of detecting disease
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Many people with cancer consider taking part in a clinical trial. Some people hope to be among the first to try a new treatment; others wish to improve cancer treatment for patients in the future; while others may simply be offered the chance and feel they have nothing to lose.
But how do you set about knowing which clinical trial to take part in? Finding a list of clinical trials is relatively easy; a simple internet search provides numerous databases of trials that are currently looking for patients (see list at end of article). It is far harder to work out which trial is best for you, taking into consideration your unique set of circumstances. And unfortunately, trials are often described using technical and scientific terminology that can be hard to interpret.
This article aims to equip you with some knowledge with which to make a more informed decision about whether to participate in a clinical trial, and to raise issues that you may wish to consider further.
Talking to your physician is an essential part of this process: he or she can provide further information and answer specific questions. All decisions should be taken in conjunction with your physician; you will never make your final decision alone. Remember, the better informed you are, the more likely you are to make the right decision for you.
Communication with your physician is essential
Clinical trials start after a new treatment has been studied carefully in the laboratory and found to be active and safe in animals. In the field of cancer research, such treatments may include:
- Cytotoxic chemotherapy (traditional anti-cancer drugs that kill dividing cells);
- Radiation therapy;
- Biological/novel therapies (eg, targeted drugs, monoclonal antibodies, vaccines);
- Combinations of the above.
Three phases of investigation are used to determine the effectiveness and safety of new treatments. Usually drugs pass through all three of these phases before they are granted a licence for wider use. Note however, some ‘high unmet need’ drugs are given conditional approval based on Phase II.
Phase I trials (also known as “first into man”) involve a small number of patients or healthy volunteers, and aim to determine the safety and highest tolerated dose of the new treatment. For cytotoxic drugs, Phase I trials are usually performed in patients with a variety of advanced cancers (ie, cancer that has spread beyond the initial tumor site) who have no remaining treatment options open to them, or cannot tolerate existing drugs. For some of the newer anti-cancer drugs that are less toxic, however, the initial studies may be undertaken in healthy volunteers. Phase I trials also help researchers understand how the drug is processed by the body.
Issues to consider in phase I trials- Although many side effects are predicted by animal work, it is impossible to know in advance whether a new treatment could cause harmful side effects in patients
- Safety is a prime consideration and you will be monitored very closely
- Usually carried out in clinical research units at specialist hospitals
- Cytotoxic drugs can cause multiple side effects and are usually only tested in patients with advanced disease who have no remaining treatment options open to them, or cannot tolerate existing drugs.
- Not expected to cause a dramatic improvement
- May include patients with a variety of cancers
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Phase II trials are performed in patients with a specific type of cancer, and aim to establish if the treatment is sufficiently effective without causing unacceptable side effects. A range of different dosages or dosing schedules may be tested to help the researchers find the best balance between effectiveness in treating the disease (efficacy) and unwanted or adverse side effects (toxicity). Some phase II trials are comparative (controlled), meaning that some patients receive the new treatment while others receive the standard treatment or placebo. In some trials neither the doctor nor the patient know what medication the patient is receiving (blinded).
Issues to consider in phase II trials- The researchers will know more about the treatment’s main side effects
- The treatment may be given in different ways to different people (eg, by tablet or injection)
- You will be closely monitored to see what effect the treatment has on your cancer
- If the trial is comparative, neither you nor your doctor will be able to select which treatment you receive. In addition, if the trial is blinded neither you nor your doctor will know which treatment you are receiving
- You will be assessed at intervals over several weeks or months
- This is usually phase I
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Phase III trials are performed in a larger group of patients with a single type of cancer and compare the new treatment with the best available treatment, or dummy pill (placebo) if no treatment is available. The new treatment may be tested alone or in combination with other treatments. Phase III trials generally focus on the efficacy and side effects of the new treatment, but may also examine its cost, convenience, or impact on patients’ quality of life.
Issues to consider in phase III trials- The final stage of testing so much more is known about the treatment
- Large studies involving hundreds or thousands of patients
- Usually conducted in multiple hospitals in many different countries
- Usually include patients with a single type of cancer (often at a specific stage of the disease)
- You cannot choose which treatment you receive
- You will be assessed at intervals to see if your disease progresses
- May last many years depending on the type of cancer
- You may be asked about how the treatment affects your quality of life
- A positive result may lead to the treatment becoming widely available
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| For all stages of clinical trials |
Phase II and III studies involve a number of specific design and methodology requirements that govern who can take part and how the trial will be conducted. Some of the most frequently used terms are discussed here.
Controlled trials
Some phase II and most phase III trials are controlled. This means that one group of patients receives the new treatment (trial group) and one group receives a standard treatment (control group) The control group allows the new treatment to be judged against a known quantity. Alternatively, if there is no standard treatment available, the new treatment is compared to a placebo which looks like the real drug but contains no active medication. This will show that the effect of the new treatment is greater than no treatment at all.
Placebo-controlled studies are unusual in phase III cancer studies, but may be used when evaluating a combination of treatments. In this case, the trial group receives standard treatment plus new treatment, while the control group receives standard treatment plus placebo.
Randomization
Controlled trials are randomized, which means that patients are assigned to groups randomly, usually by computer. This reduces the potential for bias and ensures that the groups are evenly matched for important characteristics, for example, age, gender, and performance status that could influence the results.
Stratification
When factors that will influence the response to treatment are known, they must be taken into account when interpreting the results. Examples include patients’ age, gender, or previous treatment. Evenly distributing these factors among the groups, by separating patients into subgroups and randomly assigning treatments to patients within each subgroup, may overcome this.
Blinding
When patients are not told which group they have been allocated to, and cannot guess because all treatments look identical the trial is called a single-blind trial. Usually, the study doctors/organizers are also unaware of the treatment allocation; this is known as “double-blind”. Blinding helps reduce bias, because if you knew which treatment you were getting, it might influence how you respond. Similarly, if the researchers knew, their expectations might color how they judge your response.
Eligibility (inclusion/exclusion) criteria
Each clinical trial has strict criteria determining who can and cannot participate. In general, clinical trials don’t include children, pregnant women, people with learning difficulties, or prisoners. Beyond that, the specific conditions will depend on the type of treatment and disease being studied. The eligibility criteria may include:- Type of cancer;
- Stage of cancer;
- Previous treatment;
- Age;
- General health;
- Other medical conditions;
- Life expectancy.
Inclusion criteria are the characteristics that patients must have to be eligible to take part in a trial, while exclusion criteria are characteristics that would stop a patient from participating.
Endpoints
Endpoints are chosen before the trial begins, and the criteria for whether a drug is successful are also set before the trial starts.
Some endpoints are related to the effectiveness of the treatment in treating the cancer and/or prolonging survival (see box below), while others measure the safety or toxicity of the treatment. Less often, endpoints relate to the treatment’s cost-effectiveness or impact on patients’ quality of life.
Common efficacy endpoints - Objective response to treatment – whether the cancer shrinks, or disappears
- Complete response – the detectable cancer completely disappears for at least four weeks
- Partial response – a decrease in the tumor size by at least half for at least four weeks, without any signs of growth elsewhere in the body
- Duration of response – the period of time between a response to treatment and cancer recurrence or growth
- Time to progression – the length of time between starting treatment and the cancer progressing
- Stable disease – the tumor size staying within certain pre-defined limits ie, not growing or shrinking sufficiently to be called a progression or a response
- Progression-free survival – the time a patient lives without any evidence of their cancer progressing
- Disease-free survival – how long people are still alive and whose cancer has not come back
- Overall survival – how long people live after they have entered the trial, irrespective of whether their cancer comes back and what they die from
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Clinical trials are carefully designed to minimize the risks and maximize the benefit to all people who take part, whichever treatment they receive. They are governed by a wide variety of legal, medical, and ethical principles, including the Declaration of Helsinki, which was developed by the World Medical Association in 1964. Trials are also regulated by national guidelines set out by government authorities.
Before a trial can start, the study plan (protocol) is carefully reviewed by an independent 'ethics review committee' to ensure it meets strict ethical and scientific standards. Once the trial is underway, the ethics committee must be informed if the trial’s procedures are changed or there are unexpected side effects. The committee has the power to stop the trial at any time.
A data monitoring committee will also usually be set up to review results from the trial at certain time points as it progresses. This committee has exclusive access to the “unblinded” data and can determine whether the new treatment is performing better, worse, or the same as the control treatment. Based on this information they can recommend that the trial continues, stops early, or runs for longer than originally planned.
Potential advantages of taking part in a clinical trial include - Being one of the first people to receive a new treatment that may prove to be better than existing options
- Having more frequent and extensive monitoring during and after the study, such as extra blood tests, scans, or general check-ups
- Helping to improve cancer treatment for patients in the future
Potential drawbacks of taking part in a clinical trial include - Taking an experimental treatment carries some risk: it may be less effective and/or cause more side effects than the standard treatment
- Extra trips to the hospital or clinic can be tiring, time-consuming, and costly (although you may be reimbursed)
- You may have to do paperwork such as filling out questionnaires
- Having more check-ups causes some people to worry more or become preoccupied with having cancer
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It is sensible to try and find out as much as possible about the new treatment before choosing to participate in a clinical trial (even if you do not ultimately receive it). But much of the publicly available information will be highly technical, making it hard for non-scientists to interpret.
The best sources of information are your doctor and the study researchers, who should be able to summarize what is known – and not known – about the new treatment. For example, you could ask:
Is it already used to treat other medical conditions?
Are similar drugs already in use?
What phase of testing has it reached?
What are the known side effects (physical and emotional)?
What are the predicted side effects (based on the way the drug works?
How often does it have to be taken?
How is it administered – tablet, injection, patch?
Will it interfere with any other medications?
Do I have to alter my diet or avoid alcohol while taking it?
Is it harmful in an accidental overdose?
Who can I contact if I have a problem? Will someone be available 24 hours a day?
Know what questions to ask
If you are interested in finding out what cancer clinical trials are being planned, the websites below may be useful:
International Cancer Research Portfolio
CancerHelp UK
US National Cancer Institute
American Cancer Society
UK Children’s Cancer Study Group
International Federation of Pharmaceutical Manufacturers and Associations