Research updates
Phase III clinical trials   page 3
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2. Ethical Issues in Clinical Trials Link to the Medical Research Council web site
The Nuremberg Code
Unethical experiments on human subjects carried out in Nazi Germany have cast a shadow over medical research. German physicians experimented on thousands of prisoners in concentration camps against their will; the victims mainly died or suffered permanent damage. The most infamous experiments were done by Josef Mengele. He conducted medical experiments on twins in Auschwitz. Since World War II other scandals have been exposed, making it clear that it is not only fascist powers that are capable of such evil.

In 1946 some of the Nazi physicians (many escaped, including Mengele) were tried before the Nuremberg Military Tribunals for crimes against humanity in the so-called "Doctors' Trial". At that time there was no international law or informal statement to differentiate legal from illegal human experimentation. The trial resulted in a document that became known as the Nuremberg Code. This outlined ten points defining legitimate medical experiments on human participants. It was the beginning of an international ethical movement in medicine leading to the Declaration of Helsinki, adopted by the World Medical Association in 1964.

The Declaration of Helsinki
The Declaration of Helsinki is a statement of the 'Ethical Principles for Medical Research Involving Human Subjects'. Since 1964 it has been refined in several revisions.

Each country chooses its own approach for putting the principles into practice. In the UK we have a system of local research ethics committees (LRECs) and multicentre research ethics committees (MRECs). These committees are made up of clinicians, statisticians, other researchers, lay people and others (e.g. a legally qualified person, a religious leader). They have to approve the protocols for all clinical trials before they can begin (see page 7).

One of the key principles the research ethics committees consider is the issue of informed consent. This is enshrined in the Helsinki agreement which states that, in clinical research:

‘the doctor should obtain the patient’s freely given informed consent, preferably in writing’.
The Uncertainty Principle
The basic principle underlying a randomised controlled trial is that there is genuine uncertainty about which of the treatments is ‘better’ . As you saw on page 2, ‘better’ does not just mean ‘more effective’. Other factors such as safety, ease of use and sometimes cost (if two treatments are otherwise as good) are taken into account.

To suggest someone enters a trial the clinical community needs to be uncertain about the risks and benefits of the treatments being compared. This is implicit in the Helsinki agreement which states that:

‘Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.’

On page 7 you will see how an ongoing trial is monitored by a Data Monitoring Committee (DMC) which can recommend stopping a trial before it is due to end. They will do this either if a treatment is clearly causing problems or is clearly providing a benefit. The role of this independent committee is the subject of current research. Variations on the emphasis of the committee’s role are reflected in the different names the DMC is sometimes called e.g. Data Monitoring and Ethics Committee or Data and Safety Monitoring Committee.

Matthew Sydes is a Medical Statistician in the Cancer Division of the MRC Clinical Trials Unit. He gained a BSc in Experimental Psychology as a full-time student then studied part-time for an MSc in Applied Statistics whilst working as a Clinical Trials Manager. Matthew works as a member of various teams that are running trials to assess treatments in prostate cancer, ovarian cancer, lymphoma and some vascular diseases.

For the past two years Matthew has been involved in a major research project into Data Monitoring Committees which are independent bodies that assess ongoing clinical trials. He is keen to ensure that the medical research community makes the methodology of clinical trials clear to patients and explains how they are run in ways which protect the interests of the public at large and patients in particular.

Photo of Matt Sydes
Figure 3. Matthew Sydes of the MRC Clinical Trials Unit.
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Question 2
Imagine that you that have a brain tumour. You are invited to join a trial and need information to make a fully informed decision about whether to take part. The main purpose of the trial is to evaluate the potential benefits and risks of a new chemotherapeutic treatment.

One of your questions might be ‘What treatment will I get if I am in the control group?’ The answer is ‘The best current chemotherapy’.

What other questions might you ask?
(Try to come up with at least 5)