New endpoints in clinical trials to better serve patients

Elihu H. Estey, MD, from the Seattle Cancer Care Alliance, Seattle, WA, summarizes his talk on new endpoints for clinical trials therapies at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. He points out that for many years, the principal endpoints for the approval of drugs by both the FDA and the EMA has been an improvement in overall survival (OS) when comparing a new drug to standard of care, with only minimal consideration for effects on quality of life. In the past, when cancer drugs were seen to be successful if they induced remission and prolonged life, with a link seen between survival time and approval of drugs. Prof. Estey discusses changes in treatments, which mean that patients can live outside of remission for longer, including improved salvage therapy and supportive care, particularly antifungal therapy. He argues that patients now spend half of the time outside of remission, and half in remission, and so having overall survival as an endpoint for new drugs is not relevant: once a drug is stopped, how long the patient survives is dependent on what is done afterwards, for example which treatments are given when relapse occurs, which does not reflect the effectiveness of the initial drug. Overall survival is confounded, and not a pure endpoint. If patients request, upon relapse, to be moved to the new drug arm from the standard of care drug arm in a clinical trial, this may decrease the differences in overall survival between the arms of the clinical trial, which is not in the interest of those hoping to show that the new drug is more effective than standard of care in order to obtain approval, and so there is often a “no crossover” policy, introducing an ethical consideration against overall survival as an endpoint. On the other hand, event-free survival (EFS) / progression-free survival (PFS), which assesses only the time to relapse, allows crossover, and reduces the time before an assessment of drug efficacy can be made. Prof. Estey introduces his study determining whether there is a relationship between overall survival and event-free survival, which found that there was a correlation, with EFS being a surrogate for OS. A key problem with EFS is that this is dependent on the frequency of monitoring, and difficult to assess in patients who do not go into remission. An additional endpoint is response, which does not necessarily translate into longer survival, however there are strong arguments from patients and caregivers for this, as patients who achieve a complete remission (CR) get a better quality of life, receiving fewer transfusions and spending less time in hospital. He concludes that the best endpoint is dependent on the circumstances, for example, in a younger patient with an expectation of a cure, overall survival or event-free survival may be best, while in older patients, quality of life may more important.

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