a twinning project financed via PHARE Nicare programme


the meeting took place on 25-27 October 2000 in Hotel Tatra, Bratislava, Slovakia


State Institute for Drug Control, Slovak Republic


Medicines Evaluation Board, The Netherlands


organized a conference




as a twinning project financed via Nicare Phare programme No. SR 9708 02 01 – Health management.

In the conference with 10 speakers from the MEB 75 participants from the SIDC took part among which 37 external assessors.The conference took place in Bratislava on 25-27 september 2000.


The main goal and achieved benefit was presentation of the role of the Drug Regulatory Authority of the Members State in the European Union – MEB, The Netherlands to the representatives of the SIDC in the Slovak Republic, country in the pre-accession period, which DRA tasks in the future will be that of the DRA of the Member State. Exchange of the views in the discussion involved current EU procedures for the marketing authorisation and the assessment of the marketing authorisation application on the assessors level, including development and implementation of EU guidelines.



Plenary session


The conference was chaired by the director of SIDC, Assoc. Prof. Ľudevít Martinec, PhD. and started with plenary presentations given by

§         Prof. Dr. André Broekmans, director of the MEB
on organisation of regulatory competence in the Netherlands, role of the Medicines Evaluation Board, quality assurance in the assessment process, transparency of the marketing authorisation procedure, and challenges for the MEB in the future: to remain as an important player within the European regulatory system and to develop as a transfer point for expertise within the national context both for organisations dealing with medicinal products and for the health professionals;

§         Drs.Truus Janse-de Hoog, general coordinator of the Mutual Recognition procedures of the MEB
presented the role of the national agency in the EU in more detail about workload, timetables, organisation of the assessment of the marketing authorisation applications; focus was given to the Mutual Recognition Procedure, the role of the assessors and the role of the case managers has been discussed so as the experience about the influence of new European licencing sytems for medicinal products introduced in 1995; the importance of the presubmission meetings – regulatory advice has been discussed, too;

§         Dr. Hans van Bronswijk, CPMP member
presented the EU centralised procedure: sequence of events in the procedure, role and selection of the rapporteur; three aspects of the procedure were discussed in more detail: the European assessment Report, development of EU guidelines and Points to consideration documents and scientific advice procedure.


The fruitful discussion in the afternoon was led by the panel of representatives of the MEB, who gave the presentations and SIDC representatives

·         Assoc. Prof. Ľudevít Martinec, PhD, Director SIDC

·         Prof. Rastislav Dzúrik, MD, DrSc., Chairman of the Committee of Drugs, SIDC

·         PharmDr. Dagmar Stará, PhD, Head of the Registration and Approval Unit, SIDC

·         and all participants in the conference.


Plenary session continued next day with the presentation of

§         Prof. Dr. André Broekmans
on the European Regulatory System: legislative framework, evolution of the European system, the players within the system, the European procedures, the outcome of the procedures, transparency and accountability, credibility of the system, the gap between registration and reimbursement and new developments as regulation of the orphan medicinal products.


Workshops which followed after plenary session gave the opportunity to discuss more specific issues and on the topics of common interest additional plenary presentations were given.


Plenary presentations


§               Drs. Sabine Straus
gave the presentation on national organisation of pharmacovigilance in the Netherlands, tasks of and co-operation with local organisation for coordination of reporting of adverse events LAREB; organisation of pharmacovigilance on the EU level, activities of Pharmacovigilance Working Party of the CPMP as pharmacovigilance coordination body within EU both for the centrally approved product and involved also in discussion on PhV issue for products approved in the EU nationally


§               Drs. Martin Olling
addressed in his presentation issues related to the of bioavailability and bioequivalence assessment: relation between type of application (abridged) and essential similarity was explained, EU guidance on bioequivalence and bioavailability was presented: requirements for study design, subjects, reference product, test poduct, pharmacokinetic parameters evaluation, statistical acceptance criteria and finally decision making on bioequivalence was discussed




Clinical dossier I


chaired by Dr. Hans van Bronswijk

MUDr. František Gazdík, PhD

PharmDr. Dagmar Stará, PhD

The workshop addressed the assessment of the recombinant interferon approved via centralised procedure for the treatment of hepatitis C . Based on identical information on the product the identical SPC for the product as that in the EU has been approved in the SR. The new developments in the treatment of hepatitis C were briefly discussed, such as pegylated interferon and the combination treatment of interferon and ribavirin. Based on the Interferon dossier dose-finding, dose interval, side effects, clinical studies with two different doses and need for the studies with combination treatment were discussed.

The simplified procedure of CEECs for EU centrally approved products and its expected benefits were discussed, too.


Clinical dossier II


chaired by Dr. Hans van Bronswijk

 Drs. Lies van Vlijmen

PharmDr. Dagmar Stará, PhD


In this workshop the assessment of a contraceptive implant approved in the EU via mutual recognition procedure, where the MEB acted as reference member state and the assessment of MAA in the Slovak Republic was ongoing was discussed. In addition, general aspects of the assessment of contraceptives and products used for hormone replacement therapy were addressed. The role of the assessor involved in the MRP both when DRA is the Reference Member State andthe Comcerned Member was discussed,too. Some examples were given of extensively phrased indications, which could lead to confusion by the prescriber or patient.

The harmonisation of product information for the same sort of products was emphasized.

The modified procedure of SIDC for EU MRP approved products and its expected benefits were discussed, too.


Clinical dossier III


chaired by Dr. Barbara van Zwieten-Boot

Prof. MUDr. Rastislav Dzúrik, DrSc.

The workshop addressed the requirements forclinical trials for marketing authorisation application dossier taking into consideration CPMP/ICH guidelines. Following issues have been presented in more detail: endpoints (discussion on osteoporosis and cancer treatment), duration of clinical trials, specific groups of patients (children, elderly), clinical development; choice of control groups (placebo, no treatment, dose response, active drug, combination of these) which should be justified, need for both placebo and active control, necessity to show an assay sensitivity; fairness in comparative trials and non-inferiority trials were addressed, too. Critical assessment should be stated then in the Assessment report.


Pre-clinical dossier


chaired by Dr. ir. Sjoerdtje de Boer

Prof. MUDr. Pavol Švec, DrSc.

Prof.MUDr. Milan Kriška, DrSc.

Comprehensive explanatory presentation on the EU requirements for the preclinical dossier was given. Lively discussion was led about predictive issues of pharmacodynamic and animal toxicologic studies, pittfalls of interpretations, assessment of risk of use of medicine during pregnancy. Further issues as choice of dose, animals and test systems or value of the preclinical studies werer addressed in more detail.




chaired by Drs. Sabine Straus

MUDr. Pavol Gibala, PhD

This workshop focused on the post authorisation evaluation of the safety and risk/benefit evaluation of medicinal products. Typical pharmacovigilance activities of the National regulatory Authority and EMEA were presented so as ways how to evaluate new information. Activities of MAH, National Agencies and EMEA were addressed, too.

In the discussion safety concerns that arised after marketing authorisation of two products were discussed: one product has been approved via centralised procudure in the EU and handling of the reports has been discussed, the safety concerns about the other product led to the withdrawal of the MA of the product in the EU.




chaired by Drs. Truus Janse-de Hoog
Drs. Martin Olling

Prof. MUDr. Rastislav Dzúrik, DrSc.

PharmDr. Dagmar Stará, PhD.

The workshop addressed both legal and scientific- bioequivalence issues related to the generics.

The overview of the legal aspects of generic applications in the EU together with the comparison to the Slovak legislation was given.

Some examples of problems encountered in bioequivalence studies were presented. These were later discussed with respect to the decision on the (non) bioequivalence. Further following topics were discussed: reference product, choice of strength for the bioequivalence study, exemption from bioequivalence studies. The questions presented by the Slovak assessors are the same as those which EU assessors do have. The exchange of views and experience as helpful for the solution of problematic issues have been underlined.


Chemical – pharmaceutical dossier I: biotechnology


chaired by Dr. Marijke Lambert

Mgr. Petra Finďová

Dr. Yveta Nováková

In the first part of the workshop the assessment of centrally approved recombinant interferon as an example of a biotechnological product was discussed and differencies in the approach to the assessment of the medicinal product in The Netherlands and in Slovakia were addressed.

The second part of the workshop was dedicated to the discussion on the viral safety and the risk of transmitting of viral agents via medicinal products. Using a few case studies the opinions were shared. The discussion on the way of practical implementation of the EU/CPMP guidelines into everday life seems for the SIDC participants necessary to continue.


Chemical – pharmaceutical dossier II


chaired by Drs. Diana van Riet-Nales

Assoc.Prof. RNDr. Ján Lučanský

PhD Mgr. Marie Mlynárová,PhD

In this workshop the assessment of the dossier of a contraceptive implant, for which The Netherlands acted as the reference meber state, was used as a model for the discussion. Innovative features of the product presented a challenge for the assessors. The individual approach to the assessment was considered in relation to the possible situations: either there are guidelines which address the issue or there is no harmonised approach available for guidance in the assessment. The EU attitude to the assessment of MA, when laboratory test with the medicinal product are performed only if really necessary for the assessment of the dossier and not on a routine basis, has been later addressed, too.


Variations type I and II


chaired by Drs. Truus Janse-de Hoog

Drs. Diana van Riet-Nales

RNDr. Sylvia Lešková

Ing. Eva Svoreňová

In this Workshop on assessment of Type I and type II variations the main principles of type and type II variations were discussed. Mrs Truus Janse gave a short presentation about the internal procedures in the MEB for the assessment of type I. Most of them are dealt with by the secretariat, with the exception of new test methods. They are assessed by the chemical-pharmaceutical assessors. For Type II variations major changes in the SPC as new indications or posology are assessed by the clinical assessors. Minor changes are assessed by the secretariat.

In the second part of the Workshop Mrs Diana van Riet presented some casestudies for Type I variations. Allthough the type I variations are considered as 'minor' in practice difficult questions can arise during the assessment. Not all examples could be discussed during the Workshop but there was a lively interaction and there was a general feeling that further discussion was desirable. A common feeling was that good cooperation between secretariat and assessors was very important for a good handling of type I variations.

In addition to the formal meeting programme also informal discussions during breaks and in the evening and the opportunity to establish personal contacts among colleagues from Slovakia and The Netherlands contributed to the benefit from the conference. Both Drug regulatory authorities expressed the wish to continue in the co-operation in the future.



Abbreviations used in the text:

§         DRA    Drug Regulatory Authority

§         MA      Marketing Authorisation

§         MAA   Marketing Authorisation Application

§         MAH   Marketing Authorisation Holder