European Regulatory Filing for Medicines: Full Mixed Dossier and Hybrid Dossier
07 Jan 2019
For the Marketing Authorization Application (MAA) of any medicinal product, the European Union (EU) applicants need to mention the legal basis. These legal basis are mentioned in the Directive 2001/83/EC as amended. This directive mentions the dossier content, market exclusivity, and pediatric requirements in a significant way. This article highlight the requirements for new drugs (Article 8(3)—Full Mixed Dossier) and generic applications (Article 10(3) — Hybrid Medicinal Products).
Article 8(3)—Full Mixed Dossier
Article 8(3) also termed as Full Mixed Dossier, is a full dossier application for new drugs. In the full mixed dossier of MAA, all the data elements must come from the own studies of the applicant or from the published literature, mainly from the peer-reviewed literature. In the full mixed dossier, the applicant can’t rely on the prior product approvals as well as on the publically available regulatory approval documents i.e., European Public Assessment Reports (EPARs) or the Food and Drug Administration (FDA) Summary Basis of Approval.
The Committee for Medicinal Products for Human Use (CHMP) has also mentioned some nonclinical data requirements for the mixed MAAs in the guidelines. Preclinical data is not required if sufficient well-documented clinical experience is available to establish all aspects of clinical efficacy and safety. In case of lack of available genotoxicity data and for the specific identified risks, some additional studies may be required.
Data Protection and Market Exclusivity (8+2+1 Formula)
Mixed MAAs are covered with potential patents and covered by regulatory data protection (data exclusivity) for 8 years. This indicates that no one else can use the data of innovator for the next 8 years from the approval date. Along with this, 2 year of market exclusivity is also provided along with the regulatory data protection. Overall, no generics can be introduced in the market for next 10 years after the MAA approval. For any additional indication approval, the 10-year market exclusivity can be extended by 1 year. These periods of protection are usually summarized as the 8+2+1 formula.
Pediatric Investigational Plan: All the mixed MAA application dossiers should comply with a Pediatric Investigational Plan (PIP) for the European Medicines Agency’s Pediatric Committee (PDCO) adopted products. The PIP may include pediatric study data but the pediatric development may also be deferred or waived for the diseases that do not occur in children, or medicines that may be harmful to them. A specific list is published by the PDCO for product-specific waivers.
Article 10(3) — Hybrid Medicinal Products (Generic Drugs)
Article 10(3) contains applications for generics which differ from origin ator’s products also termed as Hybrid Dossier. For the generic application, a reference medicinal product (RefMP) approved in the European Union needs to be identified from the Common Technical Document (CTD) Module 1.5.2: Information for Generic, ‘‘Hybrid’’ or Bio-similar Applications. This RefMP should be used as an active comparator for the relative bioavailability studies or clinical efficacy studies.
In the Hybrid Dossier, reference is made for the nonclinical and clinical documentation included in the dossier of the RefMP, as well as to its Summary of Product Characteristics (SmPC). In some cases where bioequivalence cannot be demonstrated through bioavailability studies, pre-clinical tests or clinical trials can be provided.
In Hybrid Dossier, only specific data is required to establish the properties of the new product. This data is particularly relevant if there is a lack of published information in the literature and if extensive studies would be required for a mixed MAA. Under Article 10(3) additional data is required only in 3 circumstances:
- If definition of ‘generic medicinal product’ is not met
- Where bioavailability studies cannot be used to demonstrate bioequivalence
- Where, there is any change in active substances, therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference product
Data Protection and Market Exclusivity
Medicinal products filed through Hybrid Dossier are not protected with data exclusivity or market protection, as they are legally assimilated to generics. But any copy of the hybrid product will have to repeat the development of the existing product that is the applicant may need to perform studies comparing its own product to the existing hybrid product if that product has become the standard of care.
Pediatric Investigational Plan:No PIP is required for the generics even if the product is intended for a pediatric use. An application for a Pediatric Use Marketing Authorization (PUMA) for medicinal products that are exclusively developed for the use in children can use a hybrid dossier but PIP is required for this.