Abstract
ObjectivesTo provide a comprehensive characterisation of rare disease clinical trials registered in ClinicalTrials.gov, and compare against characteristics of trials in non-rare diseases.DesignRegistry based study of ClinicalTrials.gov registration entries.MethodsThe ClinicalTrials.gov registry comprised 133,128 studies registered to September 27, 2012. By annotating medical subject heading descriptors to condition terms we could identify rare and non-rare disease trials. A total of 24,088 Interventional trials registered after January 1, 2006, conducted in the United States, Canada and/or the European Union were categorised as rare or non-rare. Characteristics of the respective trials were extracted and summarised with comparative statistics calculated where appropriate.Main outcome measuresCharacteristics of interventional trials reported in the database categorised by rare and non-rare conditions to allow comparison.ResultsOf the 24,088 trials categorised 2,759 (11.5%) were classified as rare disease trials and 21,329 (88.5%) related to non-rare conditions. Despite the limitations of the database we found that rare disease trials differed to non-rare disease trials across all characteristics that we examined. Rare disease trials enrolled fewer participants (median 29 vs. 62), were more likely to be single arm (63.0% vs. 29.6%), non-randomised (64.5% vs. 36.1%) and open label (78.7% vs. 52.2%). A higher proportion of rare disease trials were terminated early (13.7% vs. 6.3%) and proportionally fewer rare disease studies were actively pursuing, or waiting to commence, enrolment (15.9% vs. 38.5%).ConclusionRare disease interventional trials differ from those in non-rare conditions with notable differences in enrolment, design, blinding and randomisation. However, clinical trials should aim to implement the highest trial design standards possible, regardless of whether diseases are rare or not.
Highlights
In the United States (US), a rare disease is defined as having a prevalence of fewer than 200,000 affected individuals [1]
Despite the limitations of the database we found that rare disease trials differed to non-rare disease trials across all characteristics that we examined
The labels used in the clinicaltrials.gov database are in some sense weakly defined and can often be interpreted differently by different users which might impact the validity of results presented here
Summary
In the United States (US), a rare disease is defined as having a prevalence of fewer than 200,000 affected individuals [1]. Kesselheim et al provide one comparative survey exploring pivotal trials in orphan versus nonorphan drug approval [4]. These authors characterised a number of preapproval trials highlighting differences in enrolment, randomisation, blinding, comparison groups and primary outcomes. Their survey was limited to oncology trials that supported successful drug approvals. The approach of Kesselheim et al was extended by Orfali et al to clinical trials of non-oncological orphan drugs compared with those of non-orphan drugs [5] These authors concluded that characteristics such as blinding, randomisation and placebo control were similar between trials of orphan vs non-orphan drugs. To our knowledge no large scale comparative survey has been undertaken to contrast rare disease trials with those in other conditions
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