Smaller, faster trials can improve cancer treatments

The introduction of personalised, targeted treatments means the traditional large-scale clinical trial is no longer always the most effective way of getting new treatments to cancer patients, Marie-Cécile Le Deley, Associate Professor of Clinical Epidemiology and Biostatistics at the Institut Gustave-Roussy, Villejuif, France told delegates at the European Multidisciplinary Cancer Congress in Stockholm on Monday (26 September).

Increased knowledge of tumour biology means common cancers are more and more being recognised as consisting of small subsets with particular abnormalities. These abnormalities might be targeted by specific drugsr2di, but the ability to test the many promising agents available is hindered by the need to invest huge resources in running a single large trial over many years, Le Deley said.

Le Deley simulated a series of two-treatment superiority trials, in which a new treatment was compared with the existing standard therapy, to forecast the survival improvements that could be expected over a 15-year period.

“We found that there were important gains in survival [using] a strategy of conducting more trials with smaller sample sizes and relaxed evidential criteria compared with those required under traditional trial designs,” Le Deley told delegates. “The downside of this approach is that we also reduce the certainty of the findings: we might select as a new temporary standard a treatment that does not work better than the existing best therapy, but the fact that we will conduct many more trials will allow such errors to be quickly remedied.”

“[Given] that many new targeted agents have fewer safety issues than the older cytotoxic (cell killing) treatments, we feel that the risk of accepting a few therapies that offer no [increased] benefit, but with a very low chance of a truly poorer outcome, for a greater long-term benefit at the end seems reasonable,” Le Deley said. “The possibility of a small number of backward steps in the series of trials should not lead us to discard the whole process. The classical, large sample-size clinical trials are designed to avoid wrong decisions, but take a very long time to reach a definitive result when the disease is rare.”

It will be difficult to persuade statisticians and regulators of the need for change. “The culture within these groups is very risk-averse,” said Le Deley. “Their conservative approach is reasonable; the higher the strength of evidence, the lower the risk of wrong decision. But in rare diseases, which could include many small subsets of cancers, this approach is counterproductive [if] many new agents become available for clinical testing."

The traditional, large-scale clinical trial will still be needed, but smaller, targeted trials should be allowed where appropriate, and these could lead to quicker results, and in the long term, greater gains.

“The other main benefit of this strategy is that it allows for the testing of a greater number of treatments. Our approach of viewing a succession of clinical trials as a whole, as opposed to looking at them trial-by-trial, may help us to move forward. Our work has shown that the current risk-averse trial design strategy is not always appropriate as patient populations become more and more specific, and hence smaller,” said Le Deley.

ECCO’s president Michael Baumann said, “The arrival of personalised medicine means that we will have to change our thinking and ways of doing many things, and trials are just one example of this.”