In 1747 James Lind, a British naval surgeon, conducted the first controlled clinical trial ever recorded. Scurvy was a major problem on British ships, leaving sailors debilitated with weakness, their gums bleeding and their hair falling out. The disease was killing more men than enemy action.
Lind used 12 sailors split into six groups of two to compare several scurvy treatments – hard cider, salts, citrus fruit, vinegar, a mixture of garlic, myrrh, mustard seed and radish root, and lucky last, seawater. Lind would later write “the results of all my experiments was, that oranges and lemons were the most effectual remedies for this distemper at sea”. While Lind’s results were largely buried and never acted on, he was on the right track – scurvy is caused by a lack of vitamin C.
International Clinical Trails Day, held on 20 May, commemorates Lind’s work and recognises that clinical trials are today central to discovering and proving the efficacy of new treatments.
But we have come a long way since 1747. No longer are people treated as guinea pigs and trials are characterised by thorough protocols, meticulous ethical and scientific evaluation, peer-review of outcomes and essentially, do no harm. Indeed, all people on clinical trials benefit from high-quality care.
In 1721, when England was in the grip of a smallpox epidemic, seven death row prisoners were injected with the disease to test an early form of vaccine. The ‘clinical trial’ was flawed and unethical. Firstly, without a control group, benchmarking against environmental factors wasn’t possible. Secondly, while the prisoners survived the ‘trial’ and were freed, they were never given the opportunity of informed consent and were dangerously at risk of injury and death. This can never happen now.
Today clinical trials are conducted under the Nuremberg Code, an outcome of the atrocities conducted by Nazi Germany in the name of science during WWII. The Code outlines 10 basic statements to protect human participants, including volunteer consent, avoidance of physical or mental injuries, as well as death, and producing beneficial results for society.
ETHICS OF CLINICAL TRIALS
Producing beneficial results for society is the keystone to the ethics of clinical trials, but even so ethical dilemmas can and do arise. During the mid-2000s, I was one of the principal investigators in a cancer treatment clinical trial that was at the centre of an ethical controversy. The trial’s purpose was to assess survival rate of a new melanoma treatment taken orally, compared to standard chemotherapy delivered by injection. Participants were either given the new treatment or received the standard treatment, as reviewed and agreed by numerous international oncologists.
As the trial progressed, it became increasingly clear that many patients on the new treatment were improving, with half experiencing a reduction in their cancers, while only 5 per cent of those on the standard treatment experienced a reduction.
It was obvious to the participants which treatment they were on, and as the results became clear those participants on the standard treatment understandably demanded access to the new treatment. However to do so would have undermined the trial’s whole purpose, which was to assess survival rates. That is, the end point of the trial was the death of the participant. Without the long-term control assessment from the trial, getting the new treatment through international and Australian regulatory controls was going to be a challenge.
Ultimately, the principal investigators were able to adjust the statistical analysis to allow an earlier read out of the results, following which all participating patients went on the new treatment. But it was only because of the trial that the treatment was eventually made widely available widely. Since then however, tumour resistance to the treatment has been discovered and continued refinements are now being researched.
Informed consent is an essential part of modern clinical trials, and it involves much more than reading and signing a form. Patients are given all the key facts about the clinical trial before signing up, including details of the trial, clinicians and staff participating, trial purpose and duration, as well as procedures, risks and potential benefits. And consent isn’t binding. You can withdraw from a clinical trial at any stage and your standard care won’t be affected.
TRIALS ARE GOOD MEDICINE
Some trials make use of a placebo that looks like the trial treatment, but which has no active therapy. The placebo acts as a control against which the clinicians can assess the trial treatment. Placebos are used only where the patient isn’t put at risk and never substitutes required standard care. That means, for example, that patients participating in cancer clinical trials will either be provided with a standard treatment as agreed by a clinical panel or will receive the trial treatment.
All clinical trials are conducted within strict, ethical guidelines. Before a trial can begin, investigating clinicians must complete a screening process. Clinical trials should never put a patient at significant risk and actually ensure that participants are on the best care.
Some evidence actually suggests that patients on clinical trials tend to do better, even if the trial treatment they are on doesn’t work as expected. This could be due to the patient selection process, which in some cases require patients to have a set health threshold, but it also may be because clinical trial patients receive high-quality, protocol-driven care.
As my colleague and head of clinical trials at the VCCC, Professor Mark Rosenthal often says, ‘clinical trial medicine is good medicine’.
TRIALS CHANGING AND ADAPTING
So, why aren’t more patients on clinical trials? Clinical trials are costly and time consuming; but there is also a lack of awareness among the public, as well as barriers to access such as distance from major hospitals where many trials take place.
In Australia, about 1,400 new clinical trials commence every year. The industry employs approximately 6,900 high skilled staff and is estimated to be worth around $1 billion to the annual economy.
But even 250 years later, we are still learning from an 18th Century naval surgeon. Modern clinical trials are commonly undertaken in two groups, the test group and the control group. Recently, we have been taking a page from Thomas Lind’s book and are starting to use multiple groups to test multiple treatments in what is a more efficient approach.
There are also programs being established to run trials through telehealth, enrol patients from routine clinical practice and extending clinical trials into a range of clinical disciplines.
Changing the way trials are designed and accessed will enable larger numbers of patients to participate, provide bigger data sets to evaluate and ultimately lead to proven new treatments. Thomas Lind would be happy.
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