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Press Release: Specific clinical trial methodology needed for rare cancers

02 Oct 2014
  • RCE calls for new criteria to be used in clinical trials on rare cancer treatments
  • Rare cancer patients need access to innovative cancer drugs

Lugano, 02 October 2014. A consensus paper (1) published in the Annals of Oncology today 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 (1). Current methodologies and regulations (2) 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 industry from developing drugs for most rare cancers.

“Unfortunately, rare cancer patients can’t wait,” says Kathy Oliver Founding Co-Director of the International Brain Tumour Alliance (IBTA), whose son Colin died of brain cancer in 2011. “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 harmonised 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 favour of relaxing rules so that new treatments can be tried,” said Mrs Oliver.

Press Conference during ESMO 2014

ESMO 2014 Press Conference: Paulo Casali, Vassilis Gonfinopoulos, Jean-Yves Blay and Markus Wartenberg discuss Rare Cancers Europe recommendations for clinical studies in rare cancers

The standard for developing a new treatment is the use of large Phase III controlled clinical trials, which need significant numbers of patients to prove the statistical significance of benefits of the drug being studied, before approval for use is given. Proving that a new treatment is effective can be very difficult. Indeed, any observation on the effect of new agents in rare cancers should be factored in for rare cancer therapies.

“Innovative approaches should be used in clinical trials for rare cancer treatments. 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, without affecting patient safety, of course,” said Dr Paolo G. Casali, Chairperson of RCE, from Istituto Nazionale Tumori, Milano, Italy.

The consensus document states that new approaches to summarise evidence are required for rare cancer studies. These include factoring in pre-clinical evidence, uncontrolled studies, observational evidence and analysis of retrospective cases (or anecdotal cases) as well as, of course, randomised clinical trials, whether large or smaller.

The RCE consensus paper addresses four major issues:

  • Clinical decision-making in rare cancers: Whilst decision-making in rare cancers should be rational, as for other conditions, patients’ attitudes towards “risk” should be taken into consideration. Regulatory agencies and local health systems should avoid discriminating against rare cancer patients by allowing a degree of uncertainty higher than usual. Innovative approaches should be encouraged, making use of all available knowledge (not only randomised clinical trials), in order to collect the best evidence as possible.
  • Study design in rare cancers: Large trials are not feasible in rare cancers. Low power randomised clinical trials, “adaptive” trials, and the like, should be considered. Research on biomarkers should be inherent to research on new drugs.  Bayesian approaches could better factor in all available evidence, including the pre-clinical one. The availability of electronic patient records, which allow measuring the effectiveness of treatments via patient reported outcomes in real world conditions, is a great opportunity, though again their use must take place in a methodologically innovative fashion.
  • 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. New treatments could be used temporarily, under the assumption that the surrogate end-point is valid, while waiting for final results.
  • Critical organisational aspects of clinical research in rare cancers: Reference Networks are needed in Europe, involving Centres of Expertise to improve the quality of care for rare cancers. Patients should be able to access information about ongoing trials easily and be encouraged to participate in them. While data protection is important, 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. Multidisciplinary, national, international and even global collaboration is vital to assess the value of new treatment strategies. 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,” emphasised Dr Casali. “Rare cancers present specific challenges and clinical trial methodology should adapt to them in order to accelerate innovation in this field. These innovative solutions may imply a higher uncertainty, which should be tolerated. 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.”



  1. Rare Cancers Europe methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann Oncol (2014) doi: 10.1093/annonc/mdu459
  2. Rare cancers are not so rare: the rare cancer burden in Europe. Rare Care Working Group. Gatta G. Eur J Cancer. 2011 Nov; 47(17):2493-511. doi: 10.1016/j.ejca.2011.08.008. Epub 2011 Oct 25 RARECARE working group
  3. EU Clinical Trials Directive

Notes to editors

For more information, PDF of the full paper or to speak to a Rare Cancers Europe spokesperson please contact Rare Cancers Europe

A meeting is planned between Rare Cancers Europe with the European Medicine Agency to discuss the RCE paper on the “Methodology of clinical studies on rare cancers” in London, United Kingdom on 3 October 2014.

Rare Cancers Europe (RCE) is a multi-stakeholder initiative dedicated to putting rare cancers firmly on the European policy agenda and to implementing 39 political and stakeholder recommendations (pdf).

Over four 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.

Last update: 02 Oct 2014

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