CROATIAN AGENCY FOR MEDICINAL PRODUCTS AND MEDICAL DEVICES
Programme: IPA 2007
Partner Country:Croatia
Area of Cooperation:Free movement of goods
TWINNING LIGHT PROJECT FICHE
“Strengthening of expert capacity in
implementation of EU legislation on medicines in the
Croatian Agency for Medicinal Products and Medical Devices”
Project budget: € 250.000
STANDARD TWINNING LIGHT PROJECT FICHE
1.Basic Information
1.1Programme:IPA 2007 – Technical Assistance Facility
1.2Twinning Number:HR/2007/IB/SO/01TL
1.3Title:Strengthening of expert capacity in implementation of EU
legislation on medicines in the Croatian Agency for Medicinal Products and Medical Devices
1.4Sector:Free movement of goods
1.5 Beneficiarycountry: Republic of Croatia
2.Objectives
2.1Overall Objective:
The overall objective is to strengthen the evaluation and quality control of medicinal products for human use in line with European standards.
2.2Project purpose:
The project purpose is to support further development and strengtheningof the operational capacity of the Croatian Agency for Medicinal products and Medical Devicesin implementation of EU legislation on medicines.
2.3 Contribution to Accession Partnership/ Stabilisation and Association Agreement/
National Programme for Integration of the Republic of Croatia into the EU (NPIEU)
National Programme for the Accession of the Republic of Croatia into the European Union – 2008 in Chapter 3.1.3.5. (page 151) outlines that the adoption of subordinate legislation pursuant to the Medicinal Products Act and further strengthening of administrative capacities are the key mid-term priorities in the field of medicinal products. Implementation of legislation and strengthening of capacities are the main goals of the proposed Twinning light project for the Croatian Agency for Medicinal Products and Medical Devices (hereinafter: the Agency) as the beneficiary institution.
The project will also contribute to the continued adoption of European standards, which is an obligation taken on by Croatia (as mentioned in: Ability to assume the obligations of membership in the document: Proposal for Council Decision on the principles, priorities and conditions contained in the Accession Partnership with Croatia and repealing decision 2006/145/EC, p. 8). As such, European directives, guidelines and similar documents regulating the field of medicinal products will be properly implemented, taking into account the relevant European norms.
It was explained in Croatia 2007 Progress report, COM(2007)663 final, page 25 that a new Medicinal Products Act entered into force in October 2007. The objective of this Act is to transpose the Community acquis on medicinal products for human use (Directive 2001/83/EC as amended by Directives 2002/98/EC, 2003/63/EC 2004/24/EC and 2004/27/EC, 2008/29/EC, Directive 2003/94/EC, and European Pharmacopoeia), on implementation of good clinical practice in clinical trials and bioequivalence studies for medicinal products for human use (Directive 2003/63/EC amending Directive 2001/83/EC, Directive 2005/28/EC, and Directive 2001/20/EC), on traditional herbal medicines (Directive 2004/24/EC) and on orphan medicinal products (Regulations No 141/2000 and 847/2000).
For legislative enforcement and full implementation of regulations (in progress), knowledge of European best practices is needed and could be learned, adopted, and followed in this project.
Croatia reported (in the same Progress report) that only limited progress has been made with regard to animal welfare. The Agency use rabbits in testing certain medicinal products to verify their pyrogen reaction. During an international symposium held in Dubrovnik in April 2008, participants acknowledged that considerable progress has been made in setting requirements, especially in Europe, but that implementation and regulatory acceptance were still key elements requiring further development, in particular for routine application in the control of biologicals. This Twinning light project aims to help the Agency take a step forward in the quality control of biologicals, without the use of animals for pyrogen testing, where possible.
In the Progress Report for 2008 it was explained that there has been some progress in sectors covered by the old approach of the Acquis, most notably in four fields, and medicinal products for human use is one of them. It states that further efforts are needed in order to reach full legislative alignment and necessary administrative capacity, particularly with regard to pharmaceuticals (and other three fields).
3.Description
3.1Background and justification:
The Republic of Croatia predicts, in its National programme for the accession into the European Union, the acquisition of the acquis communautaire in its legislation. Medicinal Products Act is in force from October 2007. Croatian Agency for Medicinal Products and Medical Devices has to implement this Act, which has been written in accordance with acquis communautaire. The Assistance of EU experts is needed for its implementation.
The Croatian Agency performs its duties on the base of knowledge and experience of its own experts. BC experts have insufficient experience in EU institutions and lack consultation with EU experts. Furthermore professional experience of respected EU experts is not available to them. This project should help in complete understanding of EU legislation and to lead to correct implementation of the European legislation in BC Agency that has been transposed into aforementioned Croatian Acts. Assistance of MS expert would be of great help.
Regulations on medicines are included in the acquis communautaire(Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use as amended by Directives 2002/98/EC, 2003/63/EC 2004/24/EC and 2004/27/EC, 2008/29/EC, Directive 2003/94/EC, Directive 2005/28/EC). This Directive is implemented in the Medicinal Product Act, but subordinate legislation on the basis of this Act is not yet renewed. In evaluation procedures BC employees use international guidelines (made by International Conference on Harmonisation, ICH), most frequently Q3B(R2): Impurities in New Drug Products and Q1E: Evaluation of Stability Data, but also other ICH guidelines, as well as EudraLex Notice to applicants and regulatory guidelines for medicinal products for human use (Pharmaceutical Legislation, Volume 2) and European Pharmacopoeia (of the Council of Europe). Although the literature is clear, an interpretation could be wrong; therefore, BC staff would prefer to have an interpretation of rules by MS experts (see: activities 1.1 and 1.2)and to learn on some examples how to apply appointed procedures (see: activity 1.3). As the postulate, the assessor has to be sure that his/her decision will be objective and fair; and if his/her ability of the guidelines interpretation was correct, the assessor would save the time for making the final conclusion after data evaluation (see also:activities 4.1 and 5.1).
Commission Directive 2003/63/EC amending Directive 2001/83/EC in Annex 1 defines Analytical, pharmacotoxicological and clinical standards and protocols in respect to the testing of medicinal products. In the Part II of that Annex, the specific marketing authorisation dossiers and requirements are proposed for medicines with well-established medicinal use, essentially similar medicinal products (i.e. generics), and similar biological medicinal products. The explanation of EU experts of the Directive (see: activities 2.1 – 2.4) should lead to the practice (see: activities 2.5 – 2.8)that would be the same in EU and the Republic of Croatia.The knowledge needed by BC Agency assessors about new chemical entities (NCE) is rather incomplete (a new chemical entity means a medicinal product that contains active substance that has not been approved in any other marketing authorization application). In Croatia there is only one Innovator Company with very small number of new chemical entities. Nevertheless, BC assessors still need to understand the documentation submitted, the guidance how to prepare it and evaluate it, how to prepare assessing report etc. Having in mind that BC staff will rarely be in the position to evaluate documentation on a new chemical entity submitted in Croatia as the first country, the basic understanding of new chemical entities regulation (given in activity 1.2)will be sufficient for nowadays.
Subordinate legislation for bioequivalence for highly-variable medicinal products has to be revised in Croatia. The function of Medicines Commission, appointed by the Head of BC Agency, but still having the position of the external advisory body, is to perform the evaluation of data on bioequivalence for marketing authorisation. The objective is to evaluate bioequivalence data in the Agency by own BC Agency experts. As the pharmaceutical assessor needs to evaluate submitted documentation dealing with determination of the bioequivalence between two products, namely a commercially available Brand product and a potential to-be-marketed Generic product, basic knowledge about this topic is expected to be gained during a seminar (see: activity 2.4), and detailed knowledge during workshop that is planed as a training on certain selected cases (see: activity 2.8).
For the marketing authorisation special provisions on medicinal products derived from human blood and plasma are given in Title X of above mentioned Directive and in Annex 1 (Part III): Particular medicinal products. Following that Directive, the obligation for evaluation of Plasma Master File for plasma-derived medicinal product and Antigen Master File for vaccines will be included in subordinate Croatian legislation in near future. BC Agency will have to implement Plasma Master File evaluation and Antigen Master File evaluation. Although BC staff has gained some experience in evaluation of these documents, MS instruction is still needed for these topics as well as for related topics for vaccines (see:activities 2.3 and 2.7).
Quality control of blood and plasma derivatives in BC Agency is mandatory for each batch manufactured in Croatia or imported into Croatia. As the part of this legal procedure, some parameters as Content of immunoglobulin A in Human normal immunoglobulin for intravenous use (IgA Ab), and Immunoglobulin potency testing are tested in BC Agency by analytical procedures different than those which will soon be introduced by the European Pharmacopoeia. The in-vivo pyrogen testing of medicines is in BC Agency still performed by using animal models and in-vitro Monocyte activation test (MAT) is not yet implemented. As the Immunoglobulin potency testing and MAT are tools for implementation of the principle of the 3Rs: reduce, refine and, finally, replace animal testing (see: Council of Europe Convention for the protection of vertebrate animals used for experimental and other scientific purposes and Directive 86/609/EEC). Experienced MS scientists would instruct BC experts since BC Agency intends to introduce these procedures (see: activities 3.1 and 3.2).
As it can be done only in MS laboratory, the study visit is planned for two persons in the same time. It is proposed by BC Agency that during the same visit the Croatian experts would be instructed how to perform MAT.After the study visit and/or discussion with MS expert, BC staff would be able to revise the observations in its related standard operation procedures (SOPs) and that would lead to better result interpretation.
As it can be seen from background described above, the goal of this project is to instruct experts of the Croatian Agency for Medicinal Products and Medical Devices to play an active role in regulatory system in full compliance with acquis communautaire. It is also necessary to take into account the application of the Treaty provision on free movement of goods. Implementation of the relevant parts of acquis in Croatian legislation and implementation of harmonized regulatory practice in Croatian Agency for Medicinal Products and Medical Devices are essential to ensure the satisfactory level of public health protection. Renewal in line with EU requirements of all marketing authorisations for pharmaceuticals which are currently on the Croatian market has not yet been completed, and thereforepractical implementation needs to be improved.
Strengthening the institutional and operational capacity of the Croatian Agency has to contribute in achieving functional National Competent Authority in the field of evaluation of human medicinal products to fulfil its national obligations as well as its future EU obligations. During its first 5 years, Croatian Agency has trained a large number of new employees, but as always, further education is needed. The further effort will have to be made regarding the education that is still needed for proper managing with obligations arising from European legislative. This is the main reason why the training of BC staff by MS experts will be of fundamental use. The BC management also needs to gain European experience and expertise. In the process of strengthening the capacity of BC Agency a wide discussion with EU experts will extend BC Agency view and help BC Agency management in re-arranging of the Agency and reducing:
- lack of sufficiently trained analysts for quality control of blood derivatives,
- lack of sufficiently trained coordinators in the field of EU registration procedures,
- lack of knowledge and practices to assess quality, non-clinical and clinical documentation following the current EU approach,
- lack of experience in the field of EU legislation and necessary organisational changes in relation to involvement into EU regulatory network.
The Croatian regulation on medicines was recently harmonized with European regulative, but assessors have no experience in it. Croatian experts are not sufficiently familiar with the current EU approach in the process of evaluation of registration dossier and preparation of the Public Assessment Reports, but soon they will have obligations to follow EU rules in the area of evaluation and control of human medicinal products.
The target of Twinning light project is to achieve the following results:
- in the area of analytical procedures - improvement of skills (result 3),
- in the area of evaluation of medicinal products – harmonizing of assessments made by Croatian experts with those made by EU experts, specially for generics, well-established used medicines, and biologicals (results 1 and 2),
- in the area of quality system: improvement of SOPs to assure sustainability of knowledge and skills (results 4 and 5).
3.2.Linked activities (other international and national initiatives):
This is the first project in the field proposed by Croatia. However, there are two projects managed by the European Medicines Agency (EMEA): the multi beneficiary project “Participation of Croatia and Turkey in EMEA activities in 2006 and 2007” and “IPA Transition Assistance Programme” which includes the participation of Croatia, the Former Yugoslav Republic of Macedonia and Turkey in EMEA activities in 2008. Representatives from the Agency participate as observers in scientific and technical EMEA non-product related meetings to prepare themselves for participation in EMEA activities and to gain the confidence of existing Member States in the Croatian system. Furthermore, this should enable the EMEA, the existing MemberStates and Republic of Croatia to be in a position to co-operate as equal, mutually respected partners.
The proposed IPA Twinning light training programme would serve to strengthen the capacity of the Croatian Agency for Medicinal Products and Medical Devices to act fully in the line with EU standards, and in particular concerning efficiency of operations and scientific standards of expertise, i.e. rational scientific assessment of quality, safety, and efficacy performed according to modern standards. In dealing with regular activities, the Agency cooperates with several agencies in the region and with the EU. Furthermore, the Agency is a member of the EDQM OMCL (Official Medicines Control Laboratory) network.
There is also a proposed project:”Preparations for eCTD and implementation of digital archival information system” (IPA TAIB 2009). It has to solve problem of accepting documentation in a new (EU proposed) formatand archiving all documentation (current – now in paper version and future eCTD). TWL IPA 2007 intends to introduce EU practice in Croatia, so it is important to learn way of (scientific, expert) evaluation of documentation independent of its format (paper or e-version). The EU practice will be implemented as Croatian practice too. IPA 2009 can be fully independent, although both projects will contribute to faster authorization of medicines.
Another IPA 2009 project(Strengthening the Institutional capacity for blood, tissues and cells, proposed by Ministry of Health and Social Welfare) has whole blood (also tissues and cells) as subject. Whole blood and finished medicinal products made from human blood and/or plasma are totally different subjects, because in the latter case blood has to be treated by manufacturing process. If, maybe, there is basically same method in quality control, it is different analytical procedure when the analyte is different (different sample preparation is always needed, calculation of result is always different etc.). Visits would not serve to train methods, but to check which reagents and from which manufacturers, what environment conditions, apparatuses and other details in protocol are used (these details are not written in analytical procedures in pharmacopoeias nor in documentation for marketing authorization).
3.3.Results:
Result 1:
BC staff familiarised with current EU legislation, directives, guidelines, rules and proceduresfor granting marketing authorisation for medicinal product for human use, as well as instructed and trained to work in line with EU practice.
Result 2:
BC staff trained to implement EU directives, rules and/or procedures for specific groups of medicinal products, preferably for quality, safety and efficacy evaluation of well-established use medicines, generics and biologicals as well as to evaluate bioequivalence data, all in line with EU practice through practical workshops.
Result 3:
BC staff trained for specific analysis in quality control of blood derivatives and other biologicals.
Result 4:
SOPs related to Marketing Authorisation improved (suggestions for changes should include conclusions of discussions between MS experts and BC staff during training).
Result5:
“Manual for BC assessors” prepared and published on local and public network for further use by assessors.
3.4Activities:
Activity related to the Result 1:
Activity 1.1.Analysing training needs – MS experts and BC management and staff would discuss the current situation in MS and BC agencies in all fields of activities relevant for the project. Round table will be organised to discuss training and workshop plan, case studies relevant to the project, as well as defining topics, relevant directives, guidelines and other materials for following activities. BC agency staff would be involved in training organisation, and actively involved in workshops (training the trainers).
Activity 1.2.Conducting training for marketingauthorisations – training should be focused on EU legislation for Marketing Authorisations (MA), Variations, and Renewals, Review of procedures for MA in EU: centralised (CP), mutual recognition (MRP), and decentralised (DCP), Basic rules for MRP/DCP assessment report, Dealing with CP, Procedures for granting a MA in Croatia after accession to EU, Rules for National procedure after accession, Implication of validity checking ofapplications for MA (all application types), variations, renewals, Post approval activities (variations, extensions, changes of labelling, Package Leaflet), Assessment of type II variations, Pre-approval and post-approval inspection (GMP, GCP, GLP)