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Experimental designs for small randomised clinical trials: an algorithm for choice

Catherine Cornu123*, Behrouz Kassai123, Roland Fisch4, Catherine Chiron5, Corinne Alberti678, Renzo Guerrini9, Anna Rosati9, Gerard Pons10, Harm Tiddens11, Sylvie Chabaud12, Daan Caudri11, Clément Ballot3, Polina Kurbatova3, Anne-Charlotte Castellan3, Agathe Bajard12, Patrice Nony23 and and the CRESim & Epi-CRESim Project Groups

Author Affiliations

1 Hôpital Louis Pradel, Centre d’Investigation Clinique, INSERM CIC201/UMR5558, 28, Avenue du Doyen Lépine, Bron 69677 cedex, France

2 CHU Lyon, Service de Pharmacologie Clinique, 8 rue Guillaume Paradin, Lyon, BP8071, 69376 cedex 08, France

3 University of Lyon 1, UMR 5558, CNRS Lyon, 8 rue Guillaume Paradin, Lyon, BP8071, 69376 cedex 08, France

4 Senior Expert Statistical Methodologist, Novartis Pharma AG, Basel CH-4056, Switzerland

5 INSERM U663 «Epilepsy in childhood and brain plasticity », Hopital Necker - Enfants Malades, Paris, France

6 Univ Paris Diderot, Sorbonne Paris Cité, 75019, Paris, France

7 AP-HP, Hôpital Robert Debré, Unité d'Epidémiologie Clinique, 75019, Paris, France

8 Inserm, CIE5, 75019, Paris, France

9 Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, Florence, Italy

10 University Paris Descartes, Inserm UMR 663, Paediatric Committee -EMA (London UK), Head PIP WP (AFSSAPS), Cochin - Saint Vincent de Paul Hospital, Paris, France

11 Erasmus University Medical Center, Sophia Children’s Hospital, P.O. box 2060, Rotterdam 3000 CB, The Netherlands

12 Unité de Biostatistique et d’Evaluation des Thérapeutiques, Centre Léon Bérard, Lyon 69373, France

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Orphanet Journal of Rare Diseases 2013, 8:48  doi:10.1186/1750-1172-8-48

Published: 25 March 2013



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. 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.


PubMed 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.


We 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.


The 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.