Adverse Drug Reaction Databases

ADVERSE DRUG REACTION DATABASES

THE NEW SYSTEM

The two agencies in Germany have established new ADR databases in their institutions. As both ADR databases are essentially similar, BfArM’s database will now be explained in more detail. After a 30-month period of development, the system went into production in March 2005, enabling the agency to fulfil legal reporting obligations towards the European Medicines Agency (EMEA) from May 2005 on. The system is fully compatible with international standards defined in the International Conference on Harmoni-sation (ICH)-E2B/M2 guidelines and supports manual data entry as well as electronic reporting according to these standards. Controlled vocabulary and classifi-cation systems have been implemented in accordance with EU requirements [e.g. Medical Dictionary for Regulatory Activities (MedDRA) in its latest version for coding medical information, ISO catalogue of country codes, WHO-Drug Dictionary and Anatomi-cal Therapeutic Chemical (ATC) classification to deal with the huge amount of drugs existing globally]. BfArM is aiming to have all ADR information about individual cases covered in the new database that is seen as a major step forwards compared with the situation so far.

The new database is not only a data entry and storage system. In addition, a workflow system has been implemented so that the case reports once entered into the database, manually or electronically, can be processed through electronic tools. This includes entry screens for single case assessment, views on the data fields in a structured way as well as access to scanned images of paper-based reports. In addition, standard forms for routine correspondence, e.g. the confirmation of receipt as well as information to third parties where appropriate, with data dynamically loaded into these forms from the database, are available.

Furthermore, a user interface for data retrieval exists that allows user-friendly stratification of data. Stan-dardised entry screens to formulate routine requests are available, but users are also allowed to perform queries on the database without using the inter-face. Retrieval results may be presented in a vari-ety of output reports. This includes various listings, summary tabulations as well as graphical presenta-tions. A set of standard reports may be amended by user-defined reports created by using a report genera-tor that is available for those who work regularly with the database and have knowledge about the details in more depth.

ELECTRONIC SUBMISSION

According to EU legislation, MAHs are obliged to send reports electronically to the responsible author-ities and the EMEA. Germany has implemented the rules in a national regulation on the basis of the German Medicines Act. This national regulation became valid on 20 October 2005, and it offers the possibility of switching to electronic reporting not at a defined date but over a period giving companies as well as regulators the chance to cope with challenges the new technology imposes.

Companies with a very low number of reports per year, defined as less than an average of ten reports annually during a period of the last 5 years, may apply for a waiver that allows paper-based reporting despite the legal obligation for electronic transmission. In this case, most reports sent to BfArM or PEI from those companies are closely monitored by both institutes. The waiver may be withdrawn if the number of reports exceed the limits in the future.

Companies that are obliged to report electronically have to undergo a test phase in which cases are submitted to a database that is only designed for user tests and developmental purposes. The tests are focused on technical aspects as well as on content of and coding in the electronic reports. These data are compared with the information provided in the paper forms normally sent. After successful comple-tion of this test that is structured similarly to the EMEA test scenario, companies shall enter into the so-called ‘production phase’. BfArM has started this phase of transmitting case reports only electronically in December 2005 with three companies and has now registered about 50 companies for electronic report-ing. The first phase of the transition period towards electronic reporting is focused on the major companies with a high number of reports so that BfArM is able to handle the huge amount of data better than before. The proportion of reports submitted by these large companies = 70 is expected to equal about 95% of all reports per year. PEI has been receiving reports electronically since February 2005, presently from 20 companies. On a daily basis, BfArM and PEI forward all new reports in their databases electronically to the EudraVigilance database run by the EMEA.

Problems that can be seen after the first months of experience are data inconsistencies across data fields and data coding that appear to be a challenge in the context of the new rules. So far, companies were obliged to transmit all relevant information in accor-dance with the legal time lines. This allows the provi-sion of data in an unstructured way even if put into appropriate report forms. The new obligations, laid down in ICH guidelines that are referenced by the applicable EU documents, go beyond these require-ments stating that information in the narrative should be reflected by accurate coding in the appropriate data fields (ICH E2D guideline). Therefore, the obligation is not only to provide but also to structure informa-tion according to the agreed international standards facilitating data retrieval to find the legendary ‘needle in the haystack’. Thus, BfArM sees its role not only in dealing with the new technologies and the huge number of reports but also in monitoring whether the requirements of structuring data are fulfilled and in providing feedback accordingly.

REPORT NUMBERS

With regard to actual figures, BfArM receives about 17 000 national case reports per year, not counting duplicate reporting and follow-ups. Report numbers from foreign countries, EU as well as non-EU, are currently declining and amount to about 120 000 annually, again not counting duplicate reporting and follow-ups. Declining numbers during the past year are because of the legal implementation of the revised EU rules for ADR reporting outlined in the so-called ‘Review 2004’. Most cases are thus received from countries outside the EU.

Unlike in other countries, BfArM receives most domestic cases through pharmaceutical companies. As far as national reports are concerned, 85% of the incoming information derive from this source. The second largest number of reports is received from drug commissions of healthcare professionals that exist for physicians (see above) as well as for pharmacists and dentists. These sources provide about 10% of national reports with the Drug Commission of the German Medical Association being the most important one. The remainder of cases is received from physicians directly (including from investigator-initiated trials). Direct consumer reports, i.e. reports from patients or their relatives, amount to an only very low number (about 100 per year). This low number sounds surpris-ing because topics of drug safety are often discussed publicly and intensively, including in lay media. On the contrary, direct consumer reporting is not encour-aged by our institute. The experience over the past decades has not shown that information has been lost by not having encouraged consumer reporting, i.e. the information has been received through other routes. The BfArM tends more to follow the interna-tional recommendations that patients should see their doctors first to seek medical advice and to trans-mit well-documented case reports that are the result of collaboration between patient and physician. This strategy is encouraged by BfArM and PEI whenever appropriate.

Most of the ADR reports refer to drugs used in cancer treatment (main ATC Group L) and those used in neurology or as analgesics (main ATC Group N). The distribution of suspect/interacting drugs mentioned in case reports – maybe more than one per case – according to the ATC classification is shown in the following figure for the year 2005 (Figure 17.1).