The diagnosis of a blood related cancer can be a devastating event for patients, families and friends. It is therefore vital for everyone to have access to reputable and understandable information to help cope with the illness. You may be asked to take part in a clinical trial if there is a suitable one running at the time of your treatment and your specialist thinks you will benefit from it. The purpose of trials is to improve treatments and reduce side-effects. They are usually called randomised trials because patients are allocated to one of the planned treatments at random in order to compare the best currently available treatment with a new treatment.
The main advantages of being in a trial are that: You may receive a new treatment that might prove to be better than standard treatment (although bear in mind there may not be any difference). You are monitored very closely to assess how you respond to treatment. Whatever course of treatment you receive you can be reassured that it is effective against your disease. It is very unlikely that you will be worse off if you are in a trial. Clinical trials follow protocols that have been reviewed by independent ethical research committees, which include representatives of the public as well as doctors and scientists.
The outcome of the trial enables doctors to identify the best treatment for a disease and thus helps improve medical care for other patients in the future. The improvements in treatment of blood cancer in recent years are the result of previous patients joining clinical trials.
What is a Clinical Trial?
Clinical trials are planned studies involving patients, which are usually designed to test new therapies. These may be new drugs that have successfully passed the required safety studies; new medical devices, for example catheters, pacemakers, etc; and new combinations of current treatments or different ways of giving the treatment. Clinical trials are always aimed at improving treatments and reducing the side effects of therapy.
New clinical trials are approved by independent ethical research committees, which include representatives of the public as well as doctors and scientists. They are run according to the procedures that are laid down in the trial protocol and all patients that participate are closely monitored. During the course of the trial, information is collected and analysed by trained researchers or clinicians. The outcome of a trial enables doctors to identify the best treatment for a disease and thus helps to improve medical care for other patients in the future.
What are the different types of clinical trials?
There are three types of clinical trials, called phase I, phase II and phase III. Each new drug or treatment has to go through all these phases of testing. Phase I trials are the earliest clinical studies that a new drug or treatment has to pass. The questions addressed in these trials concern the safety, side effects and optimum dosage and frequency of the new therapy. Only a small number of patients (up to 30) are recruited for these trials. Most patients entering phase I trials have advanced disease which has not responded to conventional treatment. The design is such that the first patient will usually be given a small dose of the new drug. The next patient will receive a higher dose if no side effects are observed. With each participating patient the dosage will gradually be increased and the effect monitored. Any side effect will be recorded and a lot of blood tests and other investigations may be necessary in order to assess the effectiveness of the new drug and how the patient's body copes with the treatment.
Phase II trials try to establish whether a treatment or new drug has any measurable effect on the disease, for example a reduction of leukaemic cells in the bone marrow. Side effects and their management, as well as the optimum dose and the type of disease the treatment tackles most efficiently are being addressed. Larger numbers of patients (greater than 100) are required for phase II trials. As in phase I trials most patients participating have advanced disease and can rarely be cured with standard treatment.
Phase III trials compare new treatments with the best currently available treatment (standard treatment). New drugs or treatments which have shown minor or no toxicity and side effects in phase I, and are effective in phase II trials, are ultimately evaluated in phase III trials. In order to observe significant differences in success rates that may be small, between the new treatment and standard treatment, large numbers of patients are required. Sometimes thousands of patients are needed and many different hospitals and even different countries are involved in recruiting patients to these trials.
The following points are additional safeguards for patients participating in a clinical trial:
The trial protocol is assessed and approved by an ethics committee
The running of the trial is supervised by a Data Monitoring Committee
The patient’s privacy is protected
The patient has received sufficient information about the trial before giving consent
The patient can refuse to continue the treatment at any time throughout
the trial without compromising future care.
Every new treatment carries an element of risk but the whole aim of trials is to minimise this risk for patients. In phase I and II trials not a lot is known about the treatment and its safety in people. In order to fill these gaps, patients will be very closely monitored and have lots of extra tests and scans. If at any stage the risks of a particular treatment are greater than the benefits to the patient the trial will be stopped. Patients will have to attend hospital more often which can cost time and money.
What is a randomised trial?
Most phase III trials are randomised, which means that patients entered into the trial are allocated to one of the planned treatments at random in order to compare the best currently available treatment with a new treatment. It is important to emphasise that whatever the course of treatment given to a patient it is effective against their disease. This ensures that the results are correct and unbiased, because equal numbers of patients are in each treatment group. Furthermore patients are allocated treatment regardless of their physical condition at the time. For example, if all the patients with a good chance of responding well were to receive the new treatment and all those with a poorer prognosis received the standard treatment, the results would give a completely false picture in favour of the new treatment.
How are clinical trials planned?
Doctors are required to write a protocol, which is a detailed plan of the clinical trial. The protocol includes:
An explanation why the trial is necessary
How many patients are needed in order to obtain a correct result (i. e. statistically significant)
Who should be included in the trial (eligibility)
Details of the planned treatments
Details of the tests and examinations each patient will have
How, when and what information will be collected
The protocol, once it has been approved by funding bodies and
ethics committees, will have to be used by everyone involved in
the trial to ensure that all patients are being treated the same way.
Who assesses the quality of clinical trials and approves them?
Clinical trial protocols are sent by funding bodies for external scientific review, carried out by independent people worldwide with the right experience and qualifications in order to ensure that the protocol is correct. The reviewers look out for any problems or difficulties the researchers might have overlooked. In addition, they carefully check how the results will be analysed and made public.
Once a protocol has passed the scientific review, and financial support from the funding body is secured, it has to be assessed by the local ethics committee. An ethics committee consists of independent, highly qualified people with different backgrounds, for example doctors, nurses, lawyers, members of the public and scientists. Hospitals that carry out research have an ethics committee that meets regularly to discuss and approve clinical trial protocols.
The job of the ethics committee is to ensure that:
The investigators are qualified to run the trial
The trial is well planned
The likely benefits of the new treatment outweigh the anticipated side effects
The information for patients is complete and easy to understand
Patients will be recruited correctly
Mechanisms are in place in case something goes wrong
A clinical trial can only start after the ethics committee has given approval. Once the protocol has been approved it cannot be changed by the researchers unless they notify the committee and await their approval of the changes. The ethics committee will receive advice from a Data Monitoring Committee and will stop a trial at any time if they have concerns about the welfare of the patients participating.
Who will have access to the medical records?
Only the doctor and the team treating a patient have access to the medical records. Without the patient's permission they cannot give information about the treatment to anyone else. If patients do not want anyone to know that they are participating in a trial, the doctor must ensure confidentiality.
All medical information collected about each patient during the trial has a code number on it to prevent identification and protect the patient's privacy. The only person who knows the code number and patient name is the doctor. This means that no names will appear in reports of the results or on any documentation that is sent to the Data Monitoring Committee.
It is common practice to notify a patient's GP about his/her participation in a trial so that he is aware of the treatment and knows what to do and who to contact if there are problems.
What happens during the clinical trial?
Once a clinical trial has been given the go-ahead patient recruitment, data collection, etc. will be monitored closely by the Data Monitoring Committee (DMC) until the trial closes. This committee tells researchers and clinicians how often they want a report (usually one a year) and what needs to be detailed in it. The DMC normally asks for information such as:
How many patients have been recruited and randomised
Any problems in getting patients into the trial
How many patients have withdrawn from the trial
The results to date
Any side effects that have been noticed
If any serious unexpected side effects are reported, even in just a few patients, the trial may have to be stopped immediately. The DMC considers the trial data at a very early stage and is thus able to advise whether the trial should continue, stop early or run for longer than the planned time. Apart from the annual reports, the trial co-ordinators have a duty to let the ethics committee know immediately about any unexpected side effects. The ethics committee then decides whether to:
Stop the trial immediately
Ask for changes to the protocol
Ask for the patient information sheet to be changed.
There are two reasons why a clinical trial may be stopped early by either the DMC or the ethics committee. Firstly, the new treatment has clearly shown superior effectiveness compared to the standard treatment and therefore more patients should have access to it as soon as possible. Alternatively, patients receiving the new treatment may suffer unacceptable side effects or may not benefit compared to those on standard treatment. If this is the case, the trial will close and all patients would receive standard treatment.
If the DMC thinks that the trial can prove something very useful but more patients are needed to get the results in order to verify this, it will be run for longer than planned.
After recruitment and treatment there is a follow up period of several years during which patients will have regular check-ups. The follow up period allows researchers and clinicians to find out about possible short and long-term effects the new treatment may have and whether the disease is more responsive than with standard treatment.
How are the results analysed and presented?
It can take several years to recruit people for a trial, especially in phase III trials. Usually the difference between the treatment groups is assessed approximately five years after patients have been treated. Therefore it can take that long before the results can be analysed by the trial statisticians and made public.
Different analyses may be performed depending on the questions being asked and laid out in the trial design. Most commonly in phase III cancer trials, so-called life tables or survival curves are produced which correlate the number or percentage of treated patients that survive their illness with time. The terms that are used in this respect are disease free survival (DFS) or event free survival (EFS). Usually, the time interval that is chosen for such an analysis depends on the time period over which data are collected and is called a Kaplan-Meier life table.
This graph is a reproduction of a Kaplan-Meier life table taken from the MRC Annual Review of leukaemia trials (2002). The graph shows that 64% of children and 41% of adult patients with acute myeloid leukaemia who were in the AML 12 trial were disease free five years after their treatment finished successfully. When two or more treatments are compared it is important to find out which one is better in terms of either overall survival (OS) or keeping the disease under control, i. e. the patient is free from progression.
From the statistical point of view a significant difference means that the results for the compared treatments are probably real, even when variations between patients are taken into account. Not every patient with the same disease responds equally well or fast to a certain treatment, which leads to a variation between patients in a treatment group. Quite often the difference between treatments is very small or it may turn out that there is no significant difference at all and the treatments are equally effective. This is a very important point and explains why such large numbers of patients are required in phase III trials.
What do the results mean?
Once all the information is complete, researchers and clinicians running the trial enter the test and follow-up results on to a form that is given to a team of statisticians. The statisticians analyse the results of all participating patients and pass on this information to the researchers who then write a report for publication. These reports do not give patient's names or any other information by which a patient could be identified. It is important that the results of a trial are made public in order to inform other clinicians of promising new treatments and thus help improve cancer treatment more widely. Results are usually published in medical journals and presented at meetings and conferences.
If a new drug has been used, it must be licensed before doctors are able to prescribe it. The Medicines and Health care products Regulatory Agency (MHRA) which is part of the Department of Health and the UK equivalent to the American Food and Drug Administration (FDA) is responsible for this.
How do patients find a clinical trial?
The patient's consultant will know about any local, national or international trial and will be able to tell them if they are suitable for them.
In addition there are trial databases that are accessible to the public, for example the
CancerHelp UK website from Cancer Research UK ( www.cancerhelp.org.uk, The Current Controlled Trials website:www.controlled-trials.com and the NCRN trials portfolio database:www.ncrn.org.uk Patients can search the databases for disease specific trials and get information about the trial outline, where it is carried out, who to contact, if it still recruits patients and on what criteria recruitment is based. These databases can help patients to find
trials that may be suitable. However, it must be emphasised that only the specialist knows if a particular trial is suitable for a patient or not and can either enter them directly into the trial or refer them to one of the centres involved.
Source of information is provided by Leukaemia Research
