The author is Dr Borislav Borissov, Director, Bulgarian Drug Agency, Sofia, Bulgaria. e-mail: email@example.com
* The CPMP is a scientific advisory body of the European Agency for the Evaluation of Medicinal Products (EMEA) http://www.ema.eu.int
“Omnium graduum dificillimus est primus” -The first step is the most difficult (Roman saying)
By 1997, ten countries from Central and Eastern Europe (CEE) had acquired the status of European Union Associated Countries. In order to prepare for full European Union (EU) membership and in anticipation of future adoption of EU pharmaceutical legislation, drug regulatory authorities from Bulgaria, the Czech Republic, Estonia, Hungary, Poland, Romania, Slovak Republic and Slovenia held a round of discussions on the need for harmonization.
Objectives of the talks focused on improved collaboration with EU competent bodies and updating and reform of existing administrative structures in line with the pre-accession strategy of the EU. As a primary target, CEE countries set out to improve networking, both within their own countries and with the EU. Following a meeting of CEE regulators at the International Conference of Drug Regulatory Authorities (ICDRA) in Bahrain in 1996, inauguration of activities was launched in June 1997 at a meeting of CEE drug regulatory authorities and delegates from the European Agency for the Evaluation of Medicines (EMEA), the European Commission, WHO, and European regulatory and industrial organizations.
Participants discussed the scope of EU accession in relation to their own regulatory activities and looked for ways to establish dialogue and collaboration to enhance harmonization of legislation, boost administrative capacity and achieve practical integration into EU structures. The principal outcome of the meeting was a Memorandum of Understanding stating the following principles:
1. EU Associated Countries wish to undertake intensive collaboration and cooperation both within their own countries and with the EU. A working group of representatives from participating countries will be established for the purpose of unification and information sharing.
2. Representatives of the participating countries agree to meet on a regular basis.
3. In order to encourage more intensive collaboration and promote improved exchange of information, greater involvement of representatives and experts of the EU Associated Countries in EU working parties and committees is proposed as follows:
• Inclusion of one representative in the EU Pharmaceutical Committee with observer status. Observers from the Associated countries will rotate in a commonly agreed manner.
• Inclusion of one representative in the Committee on Proprietary Medicinal Products (CPMP)* Working Groups for safety, efficacy and quality, with observer status.
• An expression of willingness by Bulgaria, Czech Republic, Estonia, Hungary, Slovak Republic and Slovenia to become EMEA Dissemination Centres.
• Willingness to join the EMEA Telematic Network.
• Readiness to discuss with the European Commission mutual recognition of good manufacturing practices (GMP), good laboratory practice (GLP) good clinical practice (GCP) and good review practice including their assessment.
4. In recognition and preparation for integration of EU processes, representatives will prepare common standard operating procedures (SOP) for automatic registration of products already licensed under the EU centralized procedure.
Collaboration Agreement between Drug Regulatory Authorities in European Union Associated Countries - CADREAC
In 1998, as a result of the foregoing activities, drug regulatory authorities from Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovak Republic and Slovenia met to sign the Collaboration Agreement between Drug Regulatory Authorities in European Union Associated Countries - CADREAC. The agreement lays down the following principles and common goals:
• to protect public health by ensuring the use of medicinal products that meet international standards of quality, efficacy and safety; and
• to ensure that relevant information is provided on these products.
A further aim of CADREAC was to intensify collaboration within the countries and with the European Commission, EMEA and drug regulatory authorities from EU member countries.
Cyprus and Turkey later joined CADREAC, thus extending the number of member countries to twelve. Other countries, including Croatia, Russia, Ukraine, Belarus, Moldova, Yugoslavia and Switzerland, have participated as observers in annual meetings.
The mission of CADREAC is to facilitate the smooth transition of regulatory conditions in EU associated countries to achieve regulatory standards and acquis communautaire* by:
• Implementation of EU regulatory standards.
• Involvement in professional activities within EU.
• Introduction of mutually recognized procedures.
• Development of common strategies.
• Organization of regulatory meetings.
• Exchange of informatio.
* Acquis communautaire combines the European Community legal system with European Court of Justice jurisprudence. As a condition of membership, new EU member countries are expected to adopt this as national legislation.
The latest revision of the Collaboration agreement is available on the CADREAC homepage at http://www.cadreac.org. The website is designed and maintained by the Bulgarian Drug Agency on a voluntary basis. CADREAC has a yearly rotating presidency which also hosts the Secretariat. CADREAC observers to the EU Working Groups and committees are nominated on a two-year rotational basis and each member country may have up to two observers. Observers are expected to participate proactively in the work of the groups, disseminate materials and information within CADREAC, and provide feedback to the EU bodies on behalf of CADREAC members.
In line with progressive harmonization of the pre-accession strategy, CADREAC countries comply with the “Procedure on the Granting of Marketing Authorizations by CADREAC Drug Regulatory Authorities for Medicinal Products for Human Use Authorized in the European Union Following the Centralized Procedure and the Variation and Renewal of such Marketing Authorizations”. This procedure was adopted on 17 December 1998 and the latest revision was made in 2001 which concerned retrospective inclusion of the centralized procedure (CRP) in the common CADREAC simplified system process. Until full accession to EU status, any new drug placed on CADREAC markets is considered a national procedure even if it has CRP status. CRP status within CADREAC is based on several conditions:
• The medicinal product has already been granted marketing authorization by the EMEA.
• The applicant provides parts I and II of the dossier as accepted by the EMEA and a detailed list of contents of parts III and IV. These parts are submitted on request, along with a declaration that the dossier is identical to that presented to the CRP. The applicant submits also the final CPMP Assessment Report including all annexes, the consolidated list of questions and answers and the final EU Commission Decision together with annexes. If any variations have been accepted at the time of submission, relevant details should be provided too. A periodic safety update report (PSUR) is subject to submission every 6 months for the first 2 years, annually for the next 3 years and then with each renewal. The summary of product characteristics (SPC), patient information leaflet (PIL) and the sample package text should be submitted in the national language.
• The timeframe of the assessment is recommended to be shorter than the national one, defined at 90 days, excluding any clock-stops.
Many DRAs already had experience with CRP products. This new agreement and the common approach by agencies has helped create a predictable, sustainable regulatory environment, while allowing faster access to innovative drugs approved through the CRP. In the beginning, the procedure suffered growing pains, leaving regulators and industry with unresolved issues. The EMEA played an essential role in providing scientific and regulatory support, training and additional information to CADREAC colleagues.
In April 2001, CADREAC agencies adopted the Procedure on the Granting of Marketing Authorization by CADREAC Drug Regulatory Authorities for Human Medicinal Products already authorized in EU Member States following the Decentralized Procedure - the decentralized procedure (DP) is a mutual recognition procedure and differs from CRP mainly through submission of a full dossier along with the assessment report(s), a consolidated list of questions raised by the Concerned Member State(s) and the applicant’s responses. The procedure requires:
• an updated assessment report from the Reference Member State agency;
• a periodic safety update report (PSUR) (if the dossier is submitted later than 9 months after authorization in the Reference Member State agency);
• a list of post-authorization commitments, if any; and
• a declaration from the applicant that the dossier is identical to the one submitted to the Concerned Member States for the purpose of the DP, including the variation, if applied or accepted. (The DP may be “parallel” or “repeat” depending on the time of application, and with reference to the time of application to the Reference Member State).
All CADREAC countries except Turkey have adopted the decentralized procedure. A considerable number of marketing authorizations of innovative medicinal products have already been granted through the DP within CADREAC and the procedure is, in principle, accessible for generics too.
CADREAC has forged a regulatory partnership with the EU through the accession process, transforming the challenges of negotiations into strengths and improving core competencies. CADREAC provides a forum for the identification of programming needs for on-line dialogue with the Commission, EMEA and EU member states, while implementing the acquis communautaire in the accession countries.
Overcoming logistic constraints is crucial for the successful implementation of EU legislation and practice. Firstly, a considerable amount of specific legal provisions are to be incorporated into national laws and, secondly, introducing a new regulatory philosophy in national parliaments is not always easy and often meets with conflicting industrial interests. At the time of CADREAC inauguration, EU legislation in pharmaceuticals consisted of seventeen EU Directives, along with Council Regulations and many related administrative acts, supplemented by case law decisions. This has now been consolidated into one European pharmaceutical legislation, and is currently under revision. The EU Review 2001 is available on http://pharmacos.eudra.org/F2/home.html.
Pan European Regulatory Forum
The experience and commitment already yielded by the CADREAC agencies was further developed and strengthened through the Pan European Regulatory Forum (PERF) project. PERF was an EU PHARE-funded project from 1999-2000, and provided technical support through EU member states to EU accession countries. PERF initially identified priority action areas such as good manufacturing practices (GMP), Acquis communautaire, pharmacovigilance, dossier assessment, and telematics. PERF, coordinated through the EMEA, consisted of a programme of working meetings, conferences, training, joint visits and inspections, and dissemination of information. The project was considered very useful and successful and was continued as PERF II for the 2000-2003 period.
Providing opportunities for networking and common initiatives with the EU member states authorities is one of the most important objectives of CADREAC. Sharing experiences and regulatory achievements, along with visions and values, and helping to develop one’s own regulatory authority have been the incentives and driving forces in CADREAC. In particular, there was a strong impact on staff motivation. This was achieved through training of assessors and their exposure to different regulatory environments and structures. This was complemented by implementation of knowledge and approaches in the home country, and the power of interacting and working with many teams, provision of feedback to needs assessment and continuous focus on performance improvement.
CADREAC is a successful example of a nonpolitical, technical and scientific initiative conceived to strengthen drug regulation. Under the political EU accession umbrella, it has integrated the efforts of CADREAC regulators toward complete harmonization of legislative modifications and administrative procedures necessary to guarantee compliance with current EU legislation on medicinal products. CADREAC objectives have been met through the dedication of staff, hard work and political commitment from health authorities.
The winner is the public by having medicines that comply with high scientific standards as laid down by EU legislation, and predictable, transparent pharmaceutical regulation integrated within EU legislation. For the founders and supporters of the CADREAC process, there remains the inspiration of actively building rather than simply witnessing truly historical events. After 2004, when the majority of CADREAC countries join EU as members, the model of that collaboration may be exhausted, but the achievements and successes will be available to future initiatives.
1. Dunav Press. Proceedings from the Meeting on The Collaboration Agreement between Drug Regulatory Authorities in European Union Associated Countries, 14 June 1997, Sofia, Bulgaria.
2. Procedure on the Granting of Marketing Authorizations by CADREAC Drug Regulatory Authorities for Medicinal Products for Human Use Authorized in the European Union Following the Centralized Procedure and the Variation and Renewal of such Marketing Authorizations. http://www.cadreac.org
3. Organization of a Pan European Regulatory Forum on Pharmaceuticals. Terms of Reference, PRAQIII. Pan European Regulatory Forum on Pharmaceuticals, http://perf.eudra.org.
4. Borissov, B., Popova, M., Koulaksazova, R. Transition Challenges for Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries: Focus on Bulgaria. Drug Information Journal, 35: 935-940 (2001).