We searched MEDLINE with index terms “rare diseases”, “clinical trials as topic”, “research design”, and “humans” on May 15, 2015. We did not limit our search by date or language of publication. Our search returned 133 unique references, which were screened by LB for relevance. Articles were deemed relevant if they described and discussed methods for late phase clinical trials that would be applicable for rare diseases. We also identified additional articles through searches of our files.
SeriesResearch methods to change clinical practice for patients with rare cancers
Introduction
There are no fixed criteria for the definition of a rare cancer, but a malignant disorder that has an incidence of six or less per 100 000 people per year is commonly classed as rare.1 Investigation of treatments for rare cancers is important—collectively more than 20% of all cancers diagnosed are rare, and ethically patients with a rare cancer have as much entitlement to evidence-based health care as those with common cancers.
Rare cancers were historically defined by their characteristic natural history and histopathological appearances. Increasingly, rare subtypes of common cancers are defined on the basis of molecular markers that have a specific natural history or potentially a particular response to treatment. Furthermore, subtypes can be defined by biomarkers that directly relate to key oncogenic pathways targeted by drugs or other interventions, giving rise to testable therapeutic hypotheses.2 Deep genome sequencing of cancers is increasingly revealing a few common driver aberrations but a high number of cancer genes mutated at frequencies of less than 5%.3
Increasing stratification of cancers and personalisation of treatment justifies an increasing need to identify methods for assessment of interventions that are sufficiently robust to change clinical practice in this setting. A repertoire of research methods is needed to recognise that a cancer defined as rare covers a range of incidences from the more common to extremely scarce and different methods might be appropriate at different points on the range.
The aim of our Series paper is to identify methods for the investigation of interventions for rare cancers that can affect clinical practice—an arena dominated by large phase 3 randomised controlled trials in which experimental treatments are compared with standard of care. The methods we discuss retain the core principles of clinical trials to provide unbiased evidence about the effect of interventions but are specifically relevant to small populations.
Section snippets
Challenges of conventional trials in rare cancer
The conventional phase 3 clinical trial design for affecting clinical practice is a hypothesis-testing randomised controlled trial with parallel-group treatment comparisons. Such trials are at the highest level of the hierarchy of evidence for assessing the effects of interventions on diseases. In this approach, frequentist statistical analysis is typically used to test the null hypothesis that there is no treatment effect against the alternative hypothesis that there is a treatment effect of a
Overview of methodological options
Several reviews of methods for clinical trials in rare diseases have been published, both general4, 5, 6, 7, 8, 9, 10, 11 and population-specific12, 13, 14, 15 and in the form of regulatory guidelines.16, 17 Reviews of methods as applied to rare cancers include commentaries,18 a specific review of trials underpinning approvals by the US Food and Drug Administration (FDA),19 a European consensus position paper,20 and a publication from the International Rare Cancers Initiative,21 one of the
Maximise recruitment
Recruitment can be maximised by designing and running the trial as an international collaboration and by engaging full support from the specialist centres that accumulate the rare cancer population, with the aim of near 100% recruitment of eligible patients. This approach is long established in paediatric cancer trials and is key to the International Rare Cancers Initiative,21 but is no trivial challenge. In the setting of low-quality evidence, clinical practice is probably diverse and opinions
Bayesian methods
Bayesian methods have been promoted for clinical trials in general,34, 35 but are still widely thought of as unconventional. They are advocated as an option for trials in rare diseases in reviews4, 5, 6, 7, 8, 9, 10, 12, 13 and by the European Medicines Agency16 (table 1), and are being used in three International Rare Cancers Initiative trials.22 Bayesian methods are an alternative to conventional frequentist statistical analysis and were proposed by one of the earliest papers to discuss
Singletons, baskets, and umbrellas
The n-of-1 trial52 is widely described as a research method in rare diseases (table 1), but its relevance to and application in rare cancer populations have hardly been explored. When we searched for trials on PubMed with the terms “n-of-1” and “trials”, we identified 83 reports, which were overwhelmingly of palliative interventions in the setting of non-malignant chronic diseases. Six of the studies were of supportive care interventions in cancer treatment. ClinicalTrials.gov lists 20 trials
Conclusion
Methods advocated for clinical trials in rare diseases are not necessarily applicable in rare cancers, and the choice of method used is related to where the cancer lies on a sliding scale of rarity. The approaches that we discussed will enable evidence-based clinical practice for rare cancers in the future, particularly in the rapidly developing era of molecularly defined cancers. Methods outside the conventional approach might not be ideal, but pragmatic solutions have to be sought to enable
Search strategy and selection criteria
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