A consensus paper by Rare Cancers Europe (RCE) calls for new methodologies to be applied to clinical studies in rare cancers. RCE—a multi-stakeholder initiative representing patient associations, medical societies and industry—is calling both the community of researchers and European authorities to address research methodologies and regulatory criteria that could limit rare cancer patient access to new therapies. This would mean discrimination against this patient population.

Rare cancers make up as many as 20% of new cancer cases. Current methodologies and regulations require the benefit of new treatments to be proven in a large number of patients. Given the inherently low numbers of rare cancer patients, large studies are not feasible. The risk of not building enough evidence to gain approval of new agents and the high cost of small trials may discourage the development of drugs for most rare cancers.

"Unfortunately, rare cancer patients can't wait," said Kathy Oliver, founding co-director of the International Brain Tumor Alliance (IBTA). "This consensus paper calls, among other things, for rare cancer patients to be allowed earlier access to promising experimental drugs. Rules should be relaxed. Compassionate and off-label use of new drugs should be considered.

“Of course, access to these drugs should be harmonized across Europe to ensure equitable treatment, supervised by competent bodies and the data compiled from this expanded access approach, made available to researchers. Medical decisions are usually risk averse, for many reasons, but rare cancer patients often argue in favor of relaxing rules so that new treatments can be tried," said Oliver.

"Innovative approaches should be used in clinical trials for rare cancer treatments. Study protocols today call for large number of patients. In rare cancers, which by definition affect small numbers, the methodology applied should be different, without affecting patient safety, of course," said Dr. Paolo Casali, chairperson of RCE, Istituto Nazionale Tumori, Milano, Italy.

The consensus document states that new approaches to summarize evidence are required for rare cancer studies and addresses four major issues:

• Clinical decision-making in rare cancers: Whilst decision-making should be rational, patients' attitudes towards "risk" should be taken into consideration. Innovative approaches should be encouraged.
• Study design in rare cancers: Low power randomized clinical trials, "adaptive" trials and the like, should be considered. The availability of electronic patient records, measuring the effectiveness of treatments via patient-reported outcomes in real world conditions, is a great opportunity.
• Surrogate endpoints in rare cancers: Surrogate end-points could replace clinical end-points (e.g., progression-free survival or tumor response) especially when available evidence needs to be brought to the patient's bedside, to compensate for its possible limitations.
• Critical organizational aspects of clinical research in rare cancers: Reference Networks are needed, involving Centers of Expertise to improve the quality of care for rare cancer patients. Patients should be able to access information about ongoing trials easily and be encouraged to participate. Patients should have the right to donate their clinical data and tissues for research and to give a one-time withdrawable enduring consent for their use. More cancer registries are needed. Regulatory obstacles to global investigator-driven collaborations and sharing of databases, should be overcome.

"Rare cancer patients should not be discriminated against because of the rarity of their diseases," said Casali. “Rare cancers present specific challenges and clinical trial methodology should adapt to them in order to accelerate innovation in this field. Rare cancer patients live in the hope that effective therapies will be discovered and they are willing to take risks. Their decisions and specific needs should be taken into account.”