Complementary methodologies for rare cancers: Worth discussing?

Rare Cancers Europe (RCE) is a multi stakeholder initiative promoted by ESMO (representing healthcare professionals, patients and industry) dedicated to putting rare cancers on the European political agenda. In their consensus document, RCE argue that a higher degree of uncertainty should be accepted for regulatory as well as clinically informed decision-making in rare cancers, to overcome the limitations imposed by small population trials.

Over 4 million people in the European Union are affected by rare cancers. Despite the rarity of each of the 186 rare cancers, they represent in total about 20% of all cancer cases, including all cancers in children, diagnosed in the EU27 each year. Because of the small numbers affected, it is difficult to organise large randomised clinical trials. Dr Paolo Casali, Chairperson of RCE said: "innovative approaches should be used in clinical trials for rare cancers. Study protocols today call for large number of patients. Unfortunately, in rare cancers, which by definition affect small numbers, the methodology applied should be different, allowing for more uncertainty, without affecting patient safety, of course."

The agenda for the meeting included discussions on adaptive trials, the Bayesian methodology, the role of uncontrolled studies, low power randomised trials, innovative approaches to summarise evidence, surrogate end-points, tumour response as an endpoint, the use of data from compassionate and off-label use for drugs and the role of patients in study planning and design.

Robert Hemmings, chair of the Scientific Advice Working Party at EMA explained "Whilst fully powered RCTs remain a gold-standard source of evidence about a new medicine, it is fully recognised that such investigations will not always be possible in rare diseases. In these situations, regulators are open to discuss use of complementary methodologies and evidence sources to enhance the overall evidence base. We also have the approval mechanisms to recognise uncertainties that are inherent to trials with small sample sizes in our decision making."

"EMA is ready to engage with all groups, including academic research groups. Most scientific advice requests come from industry, but we welcome and encourage requests from academia for scientific advice for academic trials. We are happy to continue our work with ESMO and RCE to understand exactly where research on rare cancers is struggling so that we can find a way forward," explained Dr. Francesco Pignatti, Head of Oncology Evaluation at EMA.

Markus Wartenberg, SPAEN patient representative who attended the meeting concluded: "Patients don't understand endpoints. Every day patients are dying. We need access to treatment, we need better treatments and for some rare cancers, we simply need 'a' treatment because there is no treatment at all."