Evaluierung der wissenschaftlichen und gesetzlichen Voraussetzungen zur Entlassung von Arzneistoffen aus der Verschreibungspflicht (Rx/OTC-Switch) in Europa und Deutschland anhand mehrerer Fallbeispiele

The market for self-medication or OTC medicinal products is steadily growing as the awareness of patients rises with regard to personal responsibility of their health. The availability of non-prescription medicinal products and the empowerment of the patients are therefore crucial for this development. As a consequence the value of switching medicinal products from prescription (Rx) to non-prescription status (OTC) is in the focus of the pharmaceutical industry in order to make innovative products available thereby closing therapeutic gaps in the self-medication area. The processes for switching of medicinal products from Rx to OTC in the European Member States are based on identical legal requirements, i.e. Art. 74 of Directive 2001/83/EC, also considering the EU Guideline on changing the classification for the supply of a medicinal product for human use or switch guideline released by the European Commission [Switch Guideline, 2006]. However, with regard to processes as well as scientific and administrative requirements heterogenous approaches could be found with differences being tremendous in the EU member states. The focus of this doctoral thesis has been the switch process in Germany, where a Marketing Authorisation Holder of a medicinal product submits an Rx/OTC-switch application to the Federal Institut for Medicinal Products and Medical Devices (Bundesinstitut für Arzneimittel und Medizinpropdukte, BfArM). Although the BfArM evaluates the switch documentation, this agency is not the decision making body in the switch process. This is finally done by a switch expert committee chaired by the BfArM and consisting of independent academic members, medical doctors and representatives of other health care professionals. This committee discusses and agrees upon a recommendation for a reclassification of an active substance- not a medicinal product- as Rx or OTC medicine. Its recommendation is then forwarded to the Ministry of Health finally being responsible for starting a legislative procedure to amend the Rx regulation which must be approved by the German Bundesrat. The switch application is based on the EU switch guideline. All preclinical and clinical data are compiled in a dossier for the purpose of switch application. However, the data package used generally consists of clinical trials performed under Rx (but not under OTC) conditions as usually the pivotal clinical trials are included in the switch dossier which have already been submitted during the registration procedure. Objective: The aim of this doctoral thesis was the evaluation of the current regulatory requirements in the EU and Germany in particular. Based on the results of this evaluation an analysis of four case-studies in order to elaborate solutions for a successful Rx/OTC switch: Methodology: The preparation of this doctoral thesis was based on a comprehensive and systematic literature research and the evaluation of the current legal and regulatory requirements for Rx/OTC switches in the EU and its Member States. This was a prerequisite to get a complete overview of the different requirements and processes for Rx/OTC switches in Europe as this information has not been available in the required detail yet. In the second part of this thesis four case-studies were analysed based on published and unpublished proprietary data related to the Rx/OTC switch procedure. These case-studies have been analyzed using different methods including the Chalmer Score, a scoring system to check the quality of randomised clinical trials [Chalmer et al., 1981]. Apart from the quality of the studies used for the switch documentation, all the data submitted within the switch application have been analysed according to the EU Switch Guideline. Based on these results the criteria for a successful switch have been elaborated. Results: Although the legal basis is identical in all EU countries, the analysis of legal and regulatory requirements in the EU revealed crucial differences in the national switch processes of the European Member States. Furthermore, according to current legislation, the generation of clinical data with an Rx medicine is currently impossible within the self-medication environment. Therefore, no clinical data under real-life conditions can be generated with OTC medications in a clinical trial setting. OTC-like studies can only be conducted after a successful OTC switch, i.e. therapy under OTC conditions with the intervention of a medical doctor in accordance with the clinical trial regulation. In the majority of the EU countries the switch applications are processed via the variation procedure with defined requirements and timelines, mainly via a Type II variation for the respective medicinal products. In addition, in more than 80% of the EU countries, the medicinal products per se are switched while in 17% of countries the active substances are classified as Rx or OTC-only. In Germany the active substances needs to be switched via a complex procedure characterized by variable timelines and low transparency to the applicant. In addition the switch is granted by the ministry of health and leads to an amendment of the regulation on Rx medicines. All four analysed case studies matched the requirements of the switch guideline with a high grade of accuracy (≥ 80%). Nevertheless, the outcome of all switch procedures was not predictable. Consequently, a conclusion on the conditions to be fulfilled for a successful switch could not be drawn. Discussion and conclusions: The requirements for an Rx/OTC switch should be harmonized within the European Member States. In addition, the generation of clinical data for the switch application in a clinical trial setting should be possible within the self-medication environment, i.e. clinical trials must be performed under self-medication conditions in pharmacies but without intervention of a medical doctor. A prerequisite would be an amendment of the EU clinical trial directive resulting in a definition of self-medication studies. Alternatively, the requirements of the switch guideline might be adapted to include the possibility to perform clinical trials of Rx medicinal products under OTC-like conditions. Furthermore, the switch procedure in Germany needs to be overhauled and harmonized with other EU countries. A sound process represents the Variation procedure according to EU Regulation 1234/2008. A type II variation for first-in-class switch and a type IB variation for so-called “me-too” products to be switched is already an established procedure in the United Kingdom. In addition, it would be reasonable to allow for switches of the respective medicinal products in contrast to the active substances. Each medicinal product should be assessed by the regulatory authority where the expertise in clinical and pre-clinical data evaluation is present. It should be considered to transfer the Switch process into the responsibility of the German regulatory authority, i.e. BfArM. Clinical and pre-clinical experts at the BfArM assessing the clinical data for new marketing authorisation should evaluate the submitted Rx/OTC switch application as well. The respective assessors know the full data of a medicinal product and therefore have the complete picture of the benefit-risk balance of a medicinal product. In conclusion, the switch processes should follow the variation procedure but not a complex process with undefined timelines as currently in place in Germany. There is no predictability for Rx/OTC switch procedures as this would be true for variation on the existing labelling documentation. The timetable of the switch process in Germany is not reliable for the applicant from a business point of view due to the fact that the switch expert committee meets only twice a year what results in maximum efforts of the marketing authorization holder to comply with those timelines. This narrow timeframe needs to be considered for the launch plan of an OTC medicinal product after a successful Rx/OTC-switch.