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A Review of Regulatory Authority Databases in Central and Eastern Europe for the Purposes of Generic Pharmaceutical Development

This article was originally published in SRA

Executive Summary

Lana Ilic Prelogovic, Gorana Perina Lakoš and Marina Krstanovic examine the availability of information that generics companies need to develop their products.

The development of generic pharmaceuticals requires a comprehensive approach in terms of the analysis of data relating to the relevant reference product or products. Important datasets that are needed for regulatory purposes include: the date of first marketing authorisation; where the product is currently on the market; and the availability of currently approved summaries of product characteristics and patient information leaflets.

For this article, we studied several regulatory databases (ie national registers) in central and eastern Europe – specifically those in Croatia, Slovenia, the Czech Republic, the Slovak Republic and Romania – and analysed the type and amount of regulatory information that is publicly available. Most of the databases include much of the necessary relevant information and are easily searchable; in some cases, however, the required information is hard to find or is simply not there.

In general, therefore, all the necessary information required by regulatory affairs personnel working in generic pharmaceutical development is now easily accessible. However, it is often necessary to conduct detailed comparisons and analyses of data obtained from different sources.

In future, based on amendments to the main European pharmaceutical directive (Directive 2001/83/EC) via Directive 2004/27/EC (specifically Article 126)1, further progress in transparency is expected. This in turn should result in an increase in the amount of data that is publicly available.

Introduction

To develop a generic product successfully and secure its approval, the company must be familiar with the whole regulatory process and the approved prescribing documents (SmPC, patient information leaflet, labelling) of the reference product. Regulatory intelligence, defined by the Regulatory Intelligence Network Group as the act of gathering and analysing publicly available regulatory information2-4, is a very useful tool for defining a regulatory approach and strategy.

In the wider sense, regulatory intelligence implies all collection and analysis of data that is aimed at securing a better understanding of the business, legal and scientific context. Having good regulatory intelligence is nowadays considered a comparative advantage, helping companies to better realise and determine their regulatory approach for newly developed generic products. Also, due to the stringency of the regulatory environment, only the most recent and up-to-date information can be considered relevant and taken into account when planning the development and regulatory approach.

Pharmaceutical development of the generic product

In the early stage of the pharmaceutical development of a generic product, it is important to identify key issues relating to the product in question, which will be covered by regulatory intelligence and which afterwards will enable determination of the critical points.

Publicly available data relating to the product in question are collected and summarised as a report in the appropriate format. Detailed analysis of data should focus on specific regions, with the aim of extracting relevant general characteristics, trends and exceptions.

It is important to emphasise that the introduction of the new molecule into the pipeline is a multidisciplinary process, involving experts from various disciplines, such as R&D, business development, quality assurance, regulatory affairs and marketing. A flow chart of all the activities that are needed during development planning and discussion is given in Figure 1.

First, what is normally discussed when the new generic product is first introduced into the portfolio (ie during the feasibility study) is the date of the first authorisation of the reference product. This information is needed for planning the possibility of placing the product on the market, ie for the calculation of the data exclusivity. Also, detailed patent searches relating to the reference product should be performed.

Second, as the basis for the pharmaceutical development of the generic product, it is necessary to know the qualitative composition of the reference product, along with other useful data such as the type of container, the shelf life and storage conditions.

Based on the available data, the regulatory affairs professional could propose an appropriate strategy and scenarios and should be in constant touch with other departments during project implementation. Moreover, once the critical parameters during product development have been recognised, the regulatory affairs department should contact the relevant regulatory authorities for scientific advice, if needed.

Regarding the subsequent defining of regulatory strategy, it is important for generics companies to be familiar with the type of approval procedure and application of the reference product, and also with the applicant, duplicate/parallel marketing authorisations, marketing authorisation holders and batch release sites approved in the procedure. Furthermore, detailed analysis and comparison of the originator’s information in the SmPCs and PILs on different markets (especially indications, posology, contraindications and undesirable effects) is essential for drafting proposals of those documents for the generic product. The availability of the assessment report of the competent authority(ies) that led to the authorisation of the reference drug product is particularly welcome.

From a marketing point of view, it is important to know whether the reference and other generic products are prescription-only medicines or over-the-counter products, their respective prices and reimbursement status and, of course, their actual presence on the market5.

Overview of registers of products authorised via CP/MRP/DCP

Information on products authorised through the European Union centralised procedure is, of course, available on the European Medicines Agency’s website (www.emea.europa.eu). The data package includes the European public assessment report, including scientific discussion as well as procedural steps taken before and after the authorisation and approved product information in all EU languages.

The register is available either on the EudraPharm website (http://eudrapharm.eu/) or on the European Commission’s website (http://ec.europa.eu/enterprise/pharmaceuticals/register/register_en.htm).

Of all the information that is available on products approved via an EU procedure (centralised, mutual recognition or decentralised), that on centrally authorised products is the most detailed, is very easily accessible and searchable and is regularly updated. Assessment reports take into account data protection so confidential information is not disclosed to the public.

Information on products authorised through mutual recognition (ie via the mutual recognition procedure or decentralised procedure) is available on the Heads of Medicines Agencies website – MRI Product Index (www.hma.eu/mri.html). Searching this database is possible only by INN (international non-proprietary name) or trade name. While it is in theory possible to search through Day 90, RMS (reference member state), CMS (concerned member state) and the application type level parameters, these search facilities are not always operational. Furthermore, in some cases – depending on the year of the procedure and the RMS – there are no links to the assessment report. In general, research through the MRI product index is time consuming, but the amount of information that can be gathered can be useful.

Product database availability in CEE

Although the majority of new chemical entities are nowadays authorised centrally, many products are still authorised either through purely national or mutual recognition procedures. Therefore, for generic companies, it is still very important to collect information from national competent authorities, primarily for the purposes of comparing SmPCs and PILs. Searching for such data can often be time consuming, as regulatory authority databases differ from one another, ie each has its own functionalities and search characteristics.

It is very important that the home site of the regulatory authority is designed in a user-friendly way; this implies that an English language version of the website is an option. The most critical issue after accessing the database is the regularity of updates.

Most of the five registers involved in our study could be searched by INN, product name, ATC code and marketing authorisation holder. Database functionality for each of the five databases is presented in Table 1.

Analysis of searchable data

As already mentioned, the quantity of searchable data is crucial for successful interpretation and integration in the development of generic products and regulatory processes. In addition to the data that are included in the SmPCs and PILs, there is some other very useful information in the registers, which facilitates the research as a whole. Such data is listed in Table 2.

The website addresses for the five regulatory authorities are as follows: Slovenia – www.zdravila.net; Slovak Republic – www.sukl.sk/sk/databazy-a-servis/databazy/vyhladavanie-v-databaze-registrovanych-liekov; Czech Republic – www.sukl.cz/modules/medication/search.php; Romania – www.anm.ro/app/nom/anm_list.asp and www.msf-dgf.ro/; and Croatia – www.almp.hr/?ln=hr&w=lijekovi.

The Former Yugoslav Republic of Macedonia has an e-document in pdf format as its online register, while Serbia, Bosnia and Herzegovina and Montenegro do not yet have any online national medicine registers. The Romanian agency website has a searchable online database with a limited quantity of data while, on the Romanian Ministry of Health website, a list of authorised products (as pdf and xls files) with the additional data (such as price and product status) is available.

Future requirements

Under Directive 2004/27/CE, further progress in transparency measures can be expected, with minutes from evaluation committee meetings as well as assessment reports to be made publicly available6. In addition to contributing to the authorities’ primary goal of protecting public health by providing information on the quality, safety and efficacy of medicines, this clause will also result in the generics industry having access to very useful information regarding potential key issues during the approval process.

From a company point of view, commercially or otherwise sensitive information often needs to be protected against public disclosure7. Even though commercially confidential information is not completely defined yet and should definitely be excluded from the general principle of transparency, considerable effort has been made to improve accessibility of agency documents relating to the authorisation and supervision of medicines8.

In addition, today it is common practice for patients to search for health information on the internet. Information available to health professionals and people working in the pharmaceutical industry should be distinguished from information disclosed to the general public both in terms of content and terminology. Therefore, more detailed information available for register users is recommended.

Finally, only co-operation between the pharmaceutical industry, regulatory authorities and healthcare professionals in exchanging relevant information will ensure faster development, and subsequently better accessibility, of medicines under the shared objective of public health protection.

Conclusion

Regulatory research is the everyday work of the regulatory professional and is especially important for generics companies. In order to be competitive and strategically oriented, a systematic approach with regard to analysis of originators’ data is essential. Data in medicines registers, available on the websites of most regulatory agencies, is a useful tool in defining a regulatory strategy. There has been considerable progress in terms of the amount of published data that is available as well as in the regularity of website updates. New legislative requirements are encouraging and promoting even more transparency in the field of medicines and this will improve access to the new usable information.

References

1. Directive 2004/27/EC, OJ, 30 April 2007, L136, 34-57, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2004_27/dir_2004_27_en.pdf

2. Brown-Tuttle M, Regulatory Intelligence Databases for Drugs, Biologics and Devices: 2007 Update, RA Focus, December 2007, 32-43

3. Brown-Tuttle M, Informational Databases for Regulatory Intelligence: A Review, RA Focus, October 2005, 34-37

4. The Regulatory Intelligence Networking Group, The Company Regulatory Intelligence (RI) Function, The Regulatory Affairs Journal – Pharma, 2007, 18(10), 671-673

5. Rønning M et al, Recommendations for national registers of medicinal products with validated ATC codes and DDD values, International Journal of Public Health, 2006, 3(1), 30-35

6. Pimpinella R, Bertini Malgarini G, Increased transparency in EU pharmaceutical code, The Lancet, 2007, 369(9556), 88-90

7. Best R, Protecting the Confidentiality of Pharmaceutical Data, The Regulatory Affairs Journal – Pharma, 2003, 14(4), 261-268

8. Schofield I, Being Open about Transparency in the EU, The Regulatory Affairs Journals – Pharma, 2009, 20(6), 345

Lana Ilic Prelogovic is head of registration in the regulatory affairs department at Belupo Inc, Zagreb, Croatia. Gorana Perina Lakoš is a pharmaceutical specialist and Marina Krstanovic, PhD, is the head of pharmaceutical documentation in the same department.

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