Background: The process of developing a drug from discovery to the market is a complex sequence of milestones that may take more than ten years. The duration, rate of failures and milestones vary greatly depending on the type of drug and the indication. Hypothesis: During the development of new molecular entities (NME) aimed for the topical treatment of inflammatory dermatological diseases (IDD), setting up an exploratory clinical development plan objective using efficient proof of concept (PoC) study designs, leads to obtaining robust and conclusive data in a short period of time, with minimal requirements of non-clinical and clinical data and minimizing the exposure of subjects participating in clinical trials to the investigational product, thus ensuring their safety. Objective: To identify the most efficient approach to explore the clinical activity of a NME for the topical treatment of IDD in terms of reliability of the results, non-clinical and clinical data requirements and in terms of exposed subjects, time to obtain activity data and investment required. Methods: A systematic review of regulatory guidelines issued by the ICH, EMA and FDA, as well as public assessment reports of topical dermatological products was done to identify the objectives of an exploratory development, and non-clinical and clinical studies required to initiate PoC studies. A systematic review of clinical trials of topical dermatological products in Aropic Eczema (AE) and Psoriasis published in the period January 2003-December 2013, to describe the type of designs used to obtain a PoC in terms of designs, number of patients, duration, type of variables and identify the most relevant clinical trial designs for PoC in AE and/or psoriasis was performed and for each type of design identified, a development plan with recommendations was proposed, estimating costs and duration and comparing the different approaches. Results: There is little information on how to plan the development of a NME for the treatment of AE or psoriasis by the topical route despite differences with respect to systemically administered products in terms of systemic exposure and safety issues may impact development plans. A total of 59 studies in AE and 40 in psoriasis were summarized and 3 main types of studies identified as relevant to assess the activity of a product applied topically on the skin: Randomized, parallel inter-subject study, Randomized, parallel, intra-subject comparison and Pharmacodynamic studies. For AE, two scenarios were proposed, where inter-subject and intra-subject studies were the PoC designs and for psoriasis a third scenario was proposed with a psoriasis plaque test as a PoC. After accounting for all previous data needed in each of the scenarios, and the particular features of development, an scenario implementing an intra-subject design for AE and with a psoriasis plaque test for psoriasis were proposed as the most efficient in terms of time and costs till a proof of clinical activity of a NME especially when it has a new mechanism of action. Conclusions: The design of the PoC study should be established early when planning the development as it will impact on the whole plan. Some approaches have been identified as more efficient although this may be influenced by different factors. A general regulatory guidance for early stage development requirements specific for topical dermatological products would be useful to adjust the amount of non-clinical testing to an extent that guaranties the safety of subjects exposed during clinical trials at the same time that avoids excessive use of resources, easing the development process and making it more efficient and predictable.
|Date of Award||25 Nov 2016|
- Consorci Corporació Sanitària Parc Taulí de Sabadell
|Supervisor||Caridad Pontes Garcia (Director) & Caridad Vilagut (Director)|