EMA, The European Drug Regulator Publishes Recommendation on Elements Required to Support the Medical Plausibility and the Assumption of Significant Benefit for an Orphan Designtion

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According to the European Parliament and Council Regulation (EC) 141/2000 (Art 5) and the Commission Regulation (EC) 847/2000 “a sponsor applying for designation of a medicinal product shall apply for designation at any stage of the development of the medicinal product before the application for marketing authorization is made”. Furthermore, in the criteria for designation (Article 3 of Regulation (EC) 141/2000) it is stated that a medicinal product shall be designated as an orphan medicinal product if its sponsor can establish that “there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Union or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition”. This Discussion Paper has two aims. Firstly, to outline the level of evidence normally required to support the medical plausibility of using the product in the applied condition, and secondly, the level of evidence required to support the assumption of significant benefit. The paper is based on the experience accumulated over recent years with several hundred orphan drug designation  applications, approximately 70% of which included a discussion on significant benefit since satisfactory methods for diagnosis, prevention or treatment existed in the European Union at the time of the submission of the application. General guidance is already available on what is considered necessary to support ‘medical plausibility’ at the time of the submission of an orphan designation application and on what is necessary for the justification of the assumption of ‘significant benefit’ if this criterion applies. This is included in the “Commission Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations  from one sponsor to another” (ENTR/6283/00) and in the “Communication from the Commission on Regulation (EC) 141/2000 of the European parliament and of the Council on orphan medicinal products” (Commission Communication 2003/C 178/02 of 29 July 2003). This discussion paper should be read in conjunction with these  documents. According to the Commission Guideline (ENTR/6283/00), the medical plausibility section should be completed for all applications. There are two aspects to “Medical Plausibility”: (1) the rationale for use of the medicinal product in the proposed orphan indication; and (2) where the orphan indication refers to a subset of a particular condition, a justification of the  medical plausibility for restricting the medicinal product in the sub-set. The ‘rationale for development’ is closely and necessarily linked with both the nature of an orphan drug as a ‘medicinal product’ and with the designation criterion set out in Article 3.1(a) of Regulation (EC) No 141/2000.

A product which is the subject of such application must be a medicinal product as defined in Article 1, Directive 2001/83/EC and consideration of the ‘medical plausibility’ at  an early stage of product development provides a means of verifying this. Article 3.1 which lays down the criteria for designation states that “a medicinal product shall be designated as an orphan medicinal product if its sponsor can establish: that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition….”. Based on this wording, the Committee for Orphan Medicinal Products (COMP) will consider the notion of ‘medical plausibility’ when assessing an application for designation.The Commission Communication (2003/C 178/02) section B.1, furthermore, recognises that the COMP may take into account available data to modify the condition under application (for example, because the Committee considers that the designatable condition is broader than the one under application). To
define a suitable condition for designation, the COMP must look at the rationale for development of the medicinal product in the proposed orphan indication. This is imperative to prevent the slicing of common conditions into invalid sub-sets (e.g. different stages of a condition such as “metastatic cancer”; subgroups of frequent diseases where the product would have interest in the rest of the disease; conditions defined based on the therapeutic use of the product such as “treatment in patientsnot responding to X”). It is important that sponsors, when preparing designation applications, are aware that this is an important issue that will be reviewed by the Committee. It should be noted that for the purpose of designation and to support the rationale for the development of the product in the proposed condition some preliminary preclinical or clinical data are generally required. A pharmacological concept, not supported by any form of evidence, would generally not be considered by the COMP as sufficient justification for the designation of the medicinal product in the proposed condition. Article 3(1)b of Regulation EC 141/2000 states that in the case where a satisfactory method of
diagnosis, prevention or treatment of the condition exists, the sponsor has to establish ‘that the medicinal product will be of significant benefit to those affected by that condition’. In the Commission Communication it is stated, “a treatment for a particular disease or condition may be associated with certain risks. These risks are balanced against the expected benefits when considering whether to grant or refuse a marketing authorisation in accordance with the criteria of safety, quality and efficacy as laid down in Directive 2001/83/EC. A marketing authorisation is granted if the benefit risk assessment is positive”. As mentioned in the Commission Regulation (EC) 847/2000, authorised medicinal products are therefore considered satisfactory methods of diagnosis, prevention or treatment. Commonly used methods of diagnosis, prevention or treatment that are not subject to marketing authorization (e.g. surgery, medical devices) may be also considered satisfactory methods, if there is scientific evidence as to the value of those methods. Significant benefit is defined in Commission Regulation (EC) 847/2000 as ‘a clinically relevant advantage or a major contribution to patient care.’ The applicant is required to justify the assumption that the medicinal product will be of significant benefit compared to the existing authorized medicinal products or methods at the time of designation. As there may be little or no clinical experience with the orphan medicinal product in question, the justification for significant benefit is likely to be made on assumptions of benefit by the applicant. As stated in the Guideline (ENTR/6283/00), at the time of designation “significant benefit should be based on well justified assumptions. Assumptions of potential benefit(s) should be plausible and where possible based on sound pharmacological principles.” In the same Guideline it is also stated that “In general a demonstration of potentially greater efficacy, an improved safety profile, and/or more favourable pharmacokinetic properties than existing methods may be considered to support the notion of significant benefit.” In addition, the Commission Communication on Regulation (EC) No 141/2000 gives some clarification on the possibility to base the significant benefit on the availability of the medicinal product (e.g. European Union availability versus availability in one Member State; supply insufficient to meet patients’ needs with the exclusion of either transient or artificial problems in supply), documented safety problems in relation to the origin of the medicinal product; serious and documented difficulties with the formulation or route of administration; long term interruption in supply of an authorized product; favorable and clinically relevant pharmacokinetic properties. In all cases the COMP is required to assess whether or not these assumptions are plausible and are supported in the application by appropriate evidence.

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