May 13, 2021
People often discuss clinical trials as if they are somehow all alike, a homogeneous process using very similar ways of testing medicines. This is far from reality. Apart from differences between the trial phases, there are big differences in how trials are designed and executed, addressing the realities of the disease and the target population.
For example, Phase III pivotal trials of a therapy for a type of cancer, designed to work in a particular molecular subset of patients, enroll potential participants who may be few and far between in the population. Such trials are very focused and attempt to gather as much information as possible from a highly characterized patient group, using complex protocols.
Because the treatments that they test are aimed to address highly specific characteristics of individual patients, they are often characterized as precision or personalized medicine. Adaptive designs are frequently used for these trials, allowing agile protocol modifications according to pre-specified rules.
At the other end of the spectrum are so-called “mega-trials” that enroll perhaps tens of thousands of participants to test multiple drugs simultaneously and in sequence. This latter kind of trial may be particularly efficient in examining drugs that are in use in other diseases to see whether they might be re-purposed. COVID-19 has given an impetus to this in a somewhat frantic search for treatments. The WHO “Solidarity” trial, performed in 405 hospitals in 30 countries, initially enrolled 11,330 adults hospitalized with COVID-19 and randomized them to one of four treatment limbs or to usual care alone. In record time, this trial established that four drugs previously promoted for the treatment of COVID-19 didn’t work, saving patients the side effects, wasted effort and cost of futile drug use.
The trial continues, through its adaptive design, to recruit patients to other treatments that will progress as possibly effective or be discarded as the trial progresses.
A further mega-trial, known as “Octopus” will test whether a range of well-known drugs that are already approved for other illnesses might help prevent and even repair the effects of degeneration and damage caused by progressive forms of multiple sclerosis (MS). This is the first multi-arm, multi-stage (or MAMS) trial for progressive MS in the world. Chief investigators have already explored the use of a commonly used cholesterol-lowering drug, simvastatin, in secondary progressive MS with encouraging results. They have also trialed three other commonly used drugs for the same condition, in a scaled-down version of “Octopus.”
To summarize, MAMS trials utilize a form of adaptive design similar to that of “Solidarity” to allow multiple drugs to be tested at once, comparing them to a single control or placebo group. The efficacy of the individual drugs in “Octopus” will be monitored by MRI scanning, with drugs that are not working dropped and substituted by others along the way.
Drugs that remain promising are continued in the trial to gather further information on efficacy and side effects. The MS Society says it expects to finalize which treatments Octopus will test first this summer and that by the fall patients with progressive MS should be able to register interest in participating.
More than a dozen drugs on the market treat the relapsing-remitting form of MS, mainly acting as anti-inflammatories to slow down the immune system’s mistaken attack on the central nervous system. But there are fewer options to help the tens of thousands of patients with progressive forms of the disease.
Repurposing well-known drugs may be a highly efficient way to discover therapies that have been hiding in plain sight and whose adverse effects are well known through long use for other indications. In addition, it has the potential to provide treatments at low cost, something of particular value for developing countries.
There is no “one size fits all” for clinical trials. Nevertheless, the extreme ends of the clinical trial spectrum, from mega-trials to trials of personalized medicines, have unique requirements for successful design and execution. All share the need for investigators, sites and participants to have immediate access to information and communication for proactive guidance to correctly identify the right participants for enrollment and help research staff correctly adhere to protocol instruction.