TY - JOUR
T1 - Directions for new developments on statistical design and analysis of small population group trials
AU - Hilgers, Ralf Dieter
AU - Roes, Kit
AU - Stallard, Nigel
AU - Alberti, Corinne
AU - Van Baal, Caroline
AU - Benda, Norbert
AU - Biesheuvel, Egbert
AU - Burmann, Carl Fredrik
AU - Bogdan, Malgorzata
AU - Comets, Emmanuelle
AU - Day, Simon
AU - Dette, Holger
AU - Dmitrienko, Alex
AU - Friede, Tim
AU - Graf, Alexandra
AU - Karlsson, Mats
AU - Koch, Armin
AU - König, Franz
AU - Van Der Lee, Johanna H.
AU - Lentz, Frederike
AU - Madan, Jason
AU - Male, Christoph
AU - Mentré, France
AU - Miller, Frank
AU - Molenberghs, Geert
AU - Neuenschwander, Beat
AU - Posch, Martin
AU - Oosterwijk, Cor
AU - Röver, Christian
AU - Senn, Stephen
AU - Torres, Ferran
AU - Zohar, Sarah
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/6/14
Y1 - 2016/6/14
N2 - Background: Most statistical design and analysis methods for clinical trials have been developed and evaluated where at least several hundreds of patients could be recruited. These methods may not be suitable to evaluate therapies if the sample size is unavoidably small, which is usually termed by small populations. The specific sample size cut off, where the standard methods fail, needs to be investigated. In this paper, the authors present their view on new developments for design and analysis of clinical trials in small population groups, where conventional statistical methods may be inappropriate, e.g., because of lack of power or poor adherence to asymptotic approximations due to sample size restrictions. Method: Following the EMA/CHMP guideline on clinical trials in small populations, we consider directions for new developments in the area of statistical methodology for design and analysis of small population clinical trials. We relate the findings to the research activities of three projects, Asterix, IDeAl, and InSPiRe, which have received funding since 2013 within the FP7-HEALTH-2013-INNOVATION-1 framework of the EU. As not all aspects of the wide research area of small population clinical trials can be addressed, we focus on areas where we feel advances are needed and feasible. Results: The general framework of the EMA/CHMP guideline on small population clinical trials stimulates a number of research areas. These serve as the basis for the three projects, Asterix, IDeAl, and InSPiRe, which use various approaches to develop new statistical methodology for design and analysis of small population clinical trials. Small population clinical trials refer to trials with a limited number of patients. Small populations may result form rare diseases or specific subtypes of more common diseases. New statistical methodology needs to be tailored to these specific situations. Conclusion: The main results from the three projects will constitute a useful toolbox for improved design and analysis of small population clinical trials. They address various challenges presented by the EMA/CHMP guideline as well as recent discussions about extrapolation. There is a need for involvement of the patients' perspective in the planning and conduct of small population clinical trials for a successful therapy evaluation.
AB - Background: Most statistical design and analysis methods for clinical trials have been developed and evaluated where at least several hundreds of patients could be recruited. These methods may not be suitable to evaluate therapies if the sample size is unavoidably small, which is usually termed by small populations. The specific sample size cut off, where the standard methods fail, needs to be investigated. In this paper, the authors present their view on new developments for design and analysis of clinical trials in small population groups, where conventional statistical methods may be inappropriate, e.g., because of lack of power or poor adherence to asymptotic approximations due to sample size restrictions. Method: Following the EMA/CHMP guideline on clinical trials in small populations, we consider directions for new developments in the area of statistical methodology for design and analysis of small population clinical trials. We relate the findings to the research activities of three projects, Asterix, IDeAl, and InSPiRe, which have received funding since 2013 within the FP7-HEALTH-2013-INNOVATION-1 framework of the EU. As not all aspects of the wide research area of small population clinical trials can be addressed, we focus on areas where we feel advances are needed and feasible. Results: The general framework of the EMA/CHMP guideline on small population clinical trials stimulates a number of research areas. These serve as the basis for the three projects, Asterix, IDeAl, and InSPiRe, which use various approaches to develop new statistical methodology for design and analysis of small population clinical trials. Small population clinical trials refer to trials with a limited number of patients. Small populations may result form rare diseases or specific subtypes of more common diseases. New statistical methodology needs to be tailored to these specific situations. Conclusion: The main results from the three projects will constitute a useful toolbox for improved design and analysis of small population clinical trials. They address various challenges presented by the EMA/CHMP guideline as well as recent discussions about extrapolation. There is a need for involvement of the patients' perspective in the planning and conduct of small population clinical trials for a successful therapy evaluation.
KW - EMA/CHMP Guideline on clinical trials in small populations
KW - Rare disease
KW - Small population clinical trials
KW - Statistical analysis
KW - Statistical design
KW - Statistical methods
UR - http://www.scopus.com/inward/record.url?scp=84975132550&partnerID=8YFLogxK
U2 - 10.1186/s13023-016-0464-5
DO - 10.1186/s13023-016-0464-5
M3 - Article
C2 - 27301273
AN - SCOPUS:84975132550
SN - 1750-1172
VL - 11
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 78
ER -