Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Maintenance / life cycle management of a MRP-product – A case study ***

Dr. Katrin Mayer (Abschlußjahr: 2006)

Language: English

The maintenance of a marketing authorisation this entails all post-approval regulatory processes to maintain the registration status of a product and to support the further development of a product - makes up the main tasks of a regulatory manager during the life cycle of a medicinal product. This Master Thesis presents a case study describing various variation procedures to notify the authorities of quality and clinical/labelling changes as well as a renewal procedure to provide an example for the legal, practical and formal aspects that need to be considered for maintenance activities.

The product in question is a parenteral imaging agent registered via MRP in all “old” EU countries in different presentations with Germany acting as the RMS. Besides the regulatory background including applicable guidance, practical considerations in the planning and preparation phase covering timelines, documentation requirements and procedural aspects are described and discussed for the different MR-procedures. Furthermore, experience in interaction with the RMS is presented.
During the first five years five Type I and three Type II CMC variations were filed. In addition three Type II labelling changes of which two were indication extensions and two TypeI administrative variations to change the address of the MAH were submitted. Overall this represents the usual number of 2-3 variations per year for a given MA.
 
As the pharmaceutical legislation was revised and amended in the last years, the regulatory environment has changed during the life cycle of the product. In particular, the revision of the Variation Regulation in October 2003 and the provisions for the new CTD format for the dossier (mandatory since November 2003) have influenced the work of the regulatory manager. The far more detailed variation catalogue of the new Variation Regulation 1084/2003 has led to an increase in quality and administrative variations, e.g. the change of MAH-name or address needs to be handled as a Type IA variation.
All major quality changes and the still on-going indication extension were filed with amendments in CTD format. The quality part of the dossier has not been transformed into a Module 3 so far. Therefore the current structure of the dossier is a mixed format containing CTD-Modules (from variations conducted since October 2003) and NTA-Parts (from the original submission and the variations before October 2003).

The procedures of the two variations to extend the indication conducted in 2002 and 2005 (still ongoing) differed very much. The first extension of the indication took more than two years. Reasons for this were capacity bottlenecks at the authority together with shortcomings at the RMS in coordinating different procedures for the same medicinal product running in parallel, but also shortcomings in the communication between company and RMS.
The second extension of indication has been processed in another regulatory environment and within a more trustful relationship with the authority. Continuous communication between the company and the RMS has ensured a smooth procedure until now.

In 2005 four Type II variations were submitted: two CMC, one indication extension and one labelling variation with a resulting high density of changes that the company and RMS had to cope with. In view of the complex quality variations which comprised several parallel changes, the BfArM proposed that the individual modifications be combined to minimise administrative work. Although deviating from the Variation Regulation which states that non-consequential changes are to be submitted as separate parallel variation applications, this practice is a welcomed submission strategy. For multi-level CMC changes this pre-discussion about possibilities to bundle single variations meanwhile has become a routine step in the preparation of variation applications.
The plan for the complex stability study supporting the site change of the product was provided to the RMS before starting the study to ensure agreement on the design.
 
The submission of draft responses to the RMS during the procedure of complex TypeII variations turned out to be useful to avoid delays or re-submissions.
According to the CRD in January 2005 the MR-renewal application was submitted in September 2004. Overall the renewal proceeded according to the guidelines; however, due to an extended clock-stop the procedure was closed more than two months after the renewal date. Therefore the subsequent planned variations had to be postponed, resulting in a delay of the overall dense variation plan for that year. The new guidance, which was updated as a result of the revised legislation, requires more documents, e.g. a Quality Overview and for a harmonised package leaflet and labelling to be submitted with the renewal application. According to the amended Community Code just one renewal is required. However, as the implementation of this provision varies between the Member States, the RMS will have to come to an agreement with the CMS whether another renewal is required for this product.

The experience from variation procedures and the renewal revealed the following aspects to be important for successful regulatory procedures:
The regulatory manager needs to be informed continuously about the changing regulatory environment and current laws and guidelines. Only then can the manager provide a documentation that complies with the scientific and formal requirements to support variations or a renewal procedure during the life cycle of a product.

The other important aspect is to establish a good relationship especially to the RMS taking the lead in all regulatory procedures of a product registered via MRP. Open and continuous communication in the preparation phase and during a procedure gives the opportunity to find out what the authority expects concerning formal and practical aspects of the submission and helps to avoid misunderstandings and to facilitate compromises to finish procedures. Only if there is a cooperative relationship and transparent communication will it be possible to make maximum use of the margin of discretion that the RMS has in its interpretation. Some significant aspects experienced were the pragmatic approach to combine single changes to one variation proposed by the RMS and the offer to pre-submit draft responses to check them for completeness before official filing to all CMSs. A direct communication between the scientific experts at the company and the authority renders the discussions more precise and efficient. Clarifying the formal requirements before submission often helps to reduce unnecessary work, e.g. number of paper copies.

During the life cycle of the product the cooperation and relationship to the RMS improved steadily as both sides strengthened their efforts to adhere to formal aspects of procedures and to support each other. All recently performed, partly still on-going variations were coordinated by the RMS perfectly on schedule. Overall the authority fulfils its role as RMS well. The ambition of the BfArM in general to operate more customer- and service-oriented after the re-structuring of the authority in 2005 and to become one of the top regulatory authorities within the EU has influenced the cooperation and procedures positively.
 
Regarding a possible extension of the MR-authorisation to the new EU countries, pros and cons to harmonise the dossier within the EU by performing a RU-MRP are discussed in this Master Thesis. An advantage would be harmonised labelling including all indications which would facilitate the logistical handling of variation packages. Timelines would be standardised also for the PSURs that need to be provided more frequently in the future. On the other side more CMSs would participate in the discussions in future MR-variation procedures and the harmonisation of the labelling is not necessarily advantageous in all new EU countries. However, since it is crucial for the companies and health authorities to achieve more harmonisation to be able to cope with the rapidly changing regulatory environment, a RU-MRP will serve this long term interest.

Pages: 73