The use of placebos in trials has a long and venerable history. Since the 18th century, when a ship doctor studying scurvy remedies conducted the first-ever clinical trial, investigators have treated control groups as an integral part of a study.
In 1784, supposedly ‘magnetised’ water was compared with plain water to determine the effects of so-called animal magnetism. And in 1799, a set of ‘active’ medical instruments were compared with a ‘dummy’ equivalent to see whether they were truly efficacious.
Since then, placebos have been a standard component of many clinical trials. Underlying this practice is a simple premise – the true pharmacological properties of a drug can be determined through trialling it alongside a placebo and subtracting the difference. If you test the drug by itself, you’ll never know whether the results are due to the active pharmaceutical ingredient or to other factors beyond its scope.
Typically, a randomised controlled trial will incorporate a placebo group alongside a treatment group, and sometimes a third group who don’t receive any treatment (real or otherwise) at all. For the most part, the groups will need to be roughly the same size. This ensures that you have a balanced counterpart from which to accurately compare results.
In recent years, however, conventional clinical trial wisdom has been shaken up. We have seen a surge of adaptive trial designs that skew far away from a 50/50 split, in a bid to keep the size of the placebo group to a minimum.
Adapt and thrive
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The concept of the ‘adaptive trial’ first emerged a decade ago, when the Food and Drug Administration introduced its Strategic Path Initiative to smooth a drug’s passage from lab to market. Defined as a "clinical study design that uses accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial", adaptive trials have grown ever more popular. In 2013, they constituted some 20% of clinical trials.
The advantages are clear – adaptive trials are far more efficient than fixed format designs in that you can review the interim data as it accrues and change the design accordingly. In a typical clinical trial, the end point must be specified in advance, which means you have little room for flexibility or exploring other avenues of research.
So far, adaptive trials have shown most success for abandoned compounds and rare diseases, as well as oncology. But at a time when R&D is rising in cost, and ever fewer drugs are being introduced into the market, there could be important benefits for chronic diseases too.
Cutting the cohort down to size
In December 2013, the Innovative Medicine Initiatives (IMI) announced the launch of a new €53m project that would pioneer new ways of studying drugs for Alzheimer’s disease. Bringing together biotech and pharmaceutical companies with universities, patient groups and regulators, this collaborative endeavour will allow several new drugs to be evaluated at once.
This, in turn, will shrink the size of the placebo group, bringing it down to around 20% of the total cohort of patients.
"In a typical clinical trial, there is a single drug and then a placebo arm and the number of patients is more or less the same," says Elisabetta Vaudano, principal scientific manager and coordinator of the Scientific Pillar at IMI. "But here we will have several treatment groups for different drugs and they will share a single placebo group."
The advantages are significant, from both an ethical and economic standpoint. A typical placebo group may include many thousands of patients, none of whom stand to benefit from the candidate drug. IMI, by contrast, seeks to ensure that as many patients as possible are exposed to a potentially effective therapy.
"There are also advantages from the point of view of trial efficiency," adds Vaudano. "Because you are exploring different compounds in parallel you can learn more about the interaction of the compound with the patient."
The IMI project will join forces with other ongoing initiatives to draw up the largest-ever register of applicable patients. These patients, who are all at different stages of the disease, will be carefully monitored so that they are able to enter a clinical trial as soon as a drug becomes available.
Once the respective trials are underway, the researchers are not tied to a rigid, predetermined methodology. They will be able to stop a treatment arm early if it is not working, reallocate particular patients to particular drugs, and focus attention on the candidates that seem to be reaping results.
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"If you stop a treatment, you don’t waste a lot of money, you don’t expose patients for a long time to something which is not effective, and you can move the patient to an arm which is more promising," says Vaudano.
Because there are no successful Alzheimer’s drugs at present, an exploratory approach of this kind, which does not define an end point, should prove highly beneficial. While there have been many previous trials for Alzheimer’s drugs, the results have been negative and the reasons for that failure inconclusive. This new design should enable the researchers to find some answers.
Pending some final approvals, the project is set to start at the beginning of 2015 and the first drugs are likely to be trialled two years later. The ultimate goal is to find a cure for Alzheimer’s disease by 2025.
For the time being, we can be clear that intractable-seeming problems require creative approaches. An adaptive trial design should enable researchers to cut costs and expedite results. Reducing the size of the placebo group, long thought to be set in stone, is just one of its many advantages.