New clinical trial designs applied to the study of orphan and rare diseases: feasibility of methodological guidance to clinical development of new treatments from a regulatory perspective
- Autores: Aránzazu Sancho López
- Directores de la Tesis: Caridad Pontes García (dir. tes.), Ferran Torres Benitez (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Fernando De Andrés Rodriguez Trelles (presid.), Inmaculada Danés (secret.), C. Avendaño Solá (voc.)
- Programa de doctorado: Programa de Doctorado en Farmacología por la Universidad Autónoma de Barcelona
- Materias:
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- Resumen
Regulatory uncertainties related to the authorizations of orphan medicinal products (OMP) are often due to unconventional clinical development, hindered by difficulties to recruit patients affected by low prevalence conditions into clinical trials. There is a huge need to strengthen support to developers on the appropriate studies to be conducted in the development of OMP in order to generate adequate evidence for the demonstration of the benefits and risks.
We hypothesized that alternative methodological approaches to the study of orphan diseases can be applied to the clinical development of new treatments, which may increase efficiency while keeping integrity and robustness of results, and that guidance to the application of such approaches to clusters of diseases or medical conditions could be given, allowing more specific regulatory guidance to researchers than those currently available.
The aims of our project included to analyse the extent of current regulatory guidance for clinical development of OMP, to select representative examples of authorized OMP and assess the applicability of a number of novel methodologies and their added value to the design and analysis of clinical trials of these medicinal products, to test the applicability and added value of new methods through simulations of alternative drug development plans, and to issue recommendations by groups of medical conditions.
The project was developed as a part of a European Collaborative Project (ASTERIX Project) funded by the European Commission with the aim to develop new methodologies for the conduct of clinical trials in small populations.
Our results show that current regulatory guidance specific to clinical development of OMP is scarce and lacks specificity. Further, an analysis of newly developed ASTERIX methods indicated that their applicability is limited when just trying to optimize the actually conducted pivotal studies. Simulations of alternative clinical developments applying novel methods revealed that the applicability and added value of novel methods and approaches is extended when the aim is set in optimising the drug development program, rather than just improving the pivotal trial as presented in isolation. Novel methods were able to address important regulatory uncertainties and increased the ability of generating robust evidence. The impact of alternative methods and approaches on relevant ethical or practical aspects varied depending on the methods applied, but when negatively impacted overall this was not done to a relevant extent. Based on these results, recommendations on applicability of methods by clusters of medical conditions were proposed.
We found that existing European regulatory references for clinical development of OMP offer limited and fragmented guidance. We also showed that novel methodologies applied to the design and analyses of clinical studies in orphan conditions are useful tools at providing a good balance of robustness and efficiency in the generated evidence, what may reduce the level of uncertainties at the time of regulatory decision-making if applied properly and early in the development planning. Therefore, the awareness and the use of these novel methodologies should be improved. Our framework, methods and recommendations represent an approach to practical and structured thought on the planning of clinical trials and analyses and could support sponsors on the appropriate studies to generate robust evidence in the scenario of small populations.
