Abstract
BackgroundSmall clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple.MethodsPubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs.ResultsWe identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs.ConclusionsThe algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.
Highlights
Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer
We performed a literature review of alternative trial designs and we summarise their main characteristics in this paper and present an algorithm that can be used to select the most appropriate design(s) for given disease-drug-outcome situations
PubMed was searched using combinations of the terms given in Table 1 in the title field, with no limitations in terms of language published up to end of 2010, to identify publications about the characteristics of different trial design methods that can be used in randomised, comparative small clinical trials, other than the standard randomised controlled trial design
Summary
Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. paediatric, geriatric, individually tailored therapies, regional subpopulations. Drugs (including orphan drugs) are developed for treating these rare diseases, and their efficacy and safety need to be evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible [6]
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