eSAE Reporting – Are the Players Ready?

European Pharmaceutical Contractor

ministry_of_economic_developmentBy: Liz Nowell, Health Decisions Ltd
Dr Alan Rawling, Assured Information Systems
Dr Michael Bowden, Health Decisions Ltd

November 2002  Volume 5 Issue 7 - Pharmacovigilance, or drug safety, has traditionally been an independent, self-contained function in many pharmaceutical companies,its primary role being to meet regulatory re­quirements. However, with increased focus from the international regulatory authorities and or­the international regulatory authorities and or­ganisations such as the International Conference on Harmonisation (ICH), this role is changing, and pharmacovigilance is increas­ingly taking a central role as a valuable source of information about the use and tolerability of the company’s products.

The volume of pharmacovigilance data, both in terms of number of individual cases and  contributing organisations is increasing annu­ally. This has led to the expectation that replacing the current paper based processes with an elec­tronic methodology will introduce efficiencies that will improve public safety and reduce the cost overhead for marketing and support of pharmaceutical products in the European Com­munity and beyond.

This paper examines the current position of the key regulatory authorities with a focus on Europe due to its imminent implementation of electronic serious adverse events (SAE) reporting and notes that the significant implications for smaller companies and those without e­capableIT Departments make compliance expensive and technically  demanding.

Why report electronically?

The volume of adverse event reports handled by pharmaceutical companies is increasing ­one large, global manufacturer that we have worked with is seeing its case volume double in number every 18 months. Part of this is due tonew product releases and increased sales vol­ume, but a significant proportion is thought tobe related to a cultural trend towards increased reporting by healthcare professionals and con­sumers.

Table 1

The number of participants – regulatory authorities, organisations such as the World Health Organisation (WHO), and pharmaceu­tical company licensing/marketing partners that require access and copies of individual SAE re­ports is also increasing.

As a consequence, the current practice of paper transmission of SAEs to regulatory au­thorities as single case reports and the subsequent re­keying of data upon receipt istime consuming, potentially inaccurate and to­tally inefficient. The FDA’s mission to “promoteand protect public health” is not met by such an outmoded practice. To overcome this, the regulatory authorities and pharmaceutical in­dustry have been working through ICH to replace paper reporting of SAEs with electronic transmission and routing of Individual Case Safety Reports (ICSRs). This is close to fruition in Europe where the implementation date has been set as January 31, 2003. Japan will fol­low later in 2003 and the FDA is expected toannounce a date soon.

Common terminology

In addition to all the guidelines, policies and procedures, electronic SAE reporting uses a lot of technical language. A glossary of some of the more common phrases is listed in Table 3.

When does it start?

The expectation from the EMEA is that compa­nies will have completed a pilot test by January 31, 2003 and will be ready for electronic re­portingfornewcases fromFebruary1onwards.

However, this is not legally enforceable. The EMEArecognises that there will be a transitional phase, but “hopes” that all companies will at least have a plan in place by that time. In addi­tion, the EMEA requires retrospective electronic reporting of all expedited cases dating back to January 1, 1995. Companies will therefore need to convert alltheir legacydata totheE2B stand­ard and transmit them to the EMEA by January 31, 2004.

The Ministry of Health and Welfare in Ja­pan has set a date of October 1, 2003 for marketed products, with no date yet for clinical reports, while in the USA industry is awaiting publication of a final rule from the FDA.

The mandatory date for the use of MedDRA for single case reports received electronicallywas January 2002, and for all adverse drug reaction reporting is January 2003.

In view of these imminent deadlines we contacted the national regulatory authorities within Europe to establish their ability to accept electronic SAE reports.

Table 2

Among the responses we received, only one regulatory authority, (INFARMED -Portugal) confirmed that it is ready to start receiving electronic ICSRs; several anticipate that they will be ready by January 31, 2003 (but is that ready to receive “test” data or “live” data?); and at least one authority admitted it would not be ready until later in 2003.

Are we actually harmonising?

On the surface the answer to this question is “yes”. However, there are significant differences in expectationandrequirement between Europe and USA. Table 4 suggests that there has been an “agreement to disagree” in several areas. EMEA The first joint pilot meeting on electronic transmission took place in April 1999. The first pilot exercise began in November 1999, ran for 12 months, and involved seven European regulatory authorities and 17 pharmaceutical companies. In later pilots, five pharmaceutical companies (Astra Zeneca, Bayer Vital, Lundbeck, Merck Sharp & Dohme and Roche), the EMEA, the UK Medicines Control Agency, and the Irish Medicines Board submitted test data, with the main focus being on testing the safety message transmission and the subsequent data validation and processing.

The EMEA has established a Joint Implementation Group, which meets quarterly and provides a forum for discussing strategic and practical issues regarding the implementation of electronic transmission in Europe. An update on the pilot activities in the other ICH regions (US and Japan) is also provided during each meeting. Participation is open to all pharmaceutical companies having a medicinal product authorised in the European Union and allows companies to participate at an early stage, even if they are not yet ready to start the actual testing with the EMEA10.

The procedure for commencing electronic transmission of ICSRs within Europe is as follows6:

  1. Contact the EMEA Electronic Transmission Coordinator, who will inform all parties accordingly
  2. Send Letter of Intent and Implementation Plan. A template is available at
  3. Review of Implementation Plan -discuss with the EMEA
  4. Obtain EudraVigilance Gateway certification for Internet communication
  5. Test phase -following the procedures outlined in the Joint Pharmacovigilance Plan for the Implementation of the ICH E2B, M1 and M2 requirements7
  6. Sign the Interchange Agreement -an agreement specifying the criteria for Regulatory Electronic Transmission of ICSRs
  7. Operational pilot phase -Commences on successful completion of the test phase. During the operational pilot phase, the currentlyestablished regulatory reporting mechanism will be further maintained for a period of three months; each authority may decide to shorten this period or extend it. This will allow comparison of the submitted data and ensure quality assurance and data consistency. The EMEA requires a paper copy of eachsubmitted ICSR inparallelwiththeelectronic version for the first six months of regular electronic submission
  8. Operational phase -on successful completion of the operational pilot phase electronic reporting will replace the currently established regulatory reporting mechanism.


The first production version (release 5.0) of EudraVigilance was launched by the EMEA on December 5, 2001. Further development to extend system functionality is scheduled during 2002/2003. The main functional components of EudraVigilance are9:

  1. EudraVigilanceGateway,asinglegatewayfor thewholeofEuropeforrapidandsecureelectronic exchange of pharmacovigilance data. This will allow Marketing Authorisation Holders (MAHs) to report to a single point within the Community from where the transactions are rerouted to the specified Member States as well as Iceland, Liechtenstein, Norway, the EMEA and the European Commission. The Gateway is considered a hub and all connectionsforboththepharmaceuticalindustryand regulatory authorities are known as spokes
  2. EudraVigilance database management system (DBMS) for the collection and effective analysis of pharmacovigilance data. The regulatory authorities have access to the database via the established secure network EudraNet and it is planned to give restricted access to the pharmaceutical industry via secure connection over the Internet as the next step10
  3. EudraVigilance Standard Terminology, with main focus on the Medical Dictionary for Regulatory Activities (MedDRA) and a Medical Product Dictionary. The deadline for pharmaceutical companies to submit simplified product information for the dictionary is September 20, 2002.

The EudraVigilance website( includes a questionnaire to all pharmaceutical companies to assessreadiness forelectronic reporting.11 No deadline has been established for completing this questionnaire although, together with submission of a Letter of Intent, it is important for EMEA planning purposes, since a great number of companies will be testing their systems at the same time. The questionnaire also provides an opportunity for companies to express their concerns and address MedDRA, Gateway, ICH and Drug Dictionary implementation issues in a systematic way.

Table 3

EMEA submission tool

The EMEA is not endorsing any particular software for electronic transmission of ICSRs. The “internal” version of the tool that EMEA is currently using is basically a simple Internet screen, which can browse your local directory to find the XML file to be sent. Once identified, the “post” button will send the file to the EMEA. Another screen allows users to read acknowledgement messages returned by the EMEA gateway.

This software is currently being extended by EMEA with a view to making it available to all manufacturers. No mention is made of charges and the implications to date are that there will be none. Such a tool will be ideal for low case volumes. Where larger volumes exist several commercial providers of alternative gateway productsexist,eg Cyclone, dsGateway, who are quoting in the region of 30,000 per annum for a two-user system.

Impact for Contract Research Organisations

The EMEA has confirmed that CROs can submit electronic ICSRs on behalf of a MAH, but the MAH must provide the EMEA with a letter from the person responsible for pharmacoviglance delegating this responsibility. For submissions through an ESTRI Gateway CROs will need to have a separate access to the EudraVigilance Gateway (a different certificate) for each MAH for whom they will be providing submissions.


The current FDA AERS system has around five customers currently active and is receiving about 15% of cases by volume electronically. Companies need to submit a duplicate paper copy until the electronic file format has been validated (Docket 92S -0251). Prior to the first submission of an electronic ICSR, companies need to notify the AERS submission coordinator at .The FDA currently uses the Templar product for its gateway, but is not endorsing the product. Any compatible software is acceptable and the pilot companies are using several tools.

ICSR attachments (literature references, autopsy reports, or hospital discharge summaries) need to be submitted by physical media (floppy disk, CDROM, or digital tape) in Portable Document Format (pdf).

Once a submission reaches the EDI Gateway and is successfully recognised and decrypted, an EDI Gateway acknowledgement will be returned to the sender.

The current procedure includes a manual review to “clean” the data. For example, companies can code using MedDRA 5.0 even though AERS uses 4.0. This is reconciled by the FDA after receipt. Even with this manual review the FDA reports much faster input speeds with electronic reporting -two days versus one week for paper reporting.

The FDA has noted the importance of planning an “alternate submission method” for situations where the FDA system is unavailable and has suggested either a MedWatch report on paper or adverse event data on CD/floppy disk.

Ministry of Health and Welfare, Japan

TheMHWmakesreference toICHon itswebsite and has published a guideline for electronic submission of ICSRs.


An E2B implementation plan

As we have discussed, the IT resource and financial implications of switching to electronic submission of SAEs can be both expensive and technically demanding. The first need is to evaluate the current pharmacovigilance business process within the company and assess current database(s) for E2B (and other regulatory) capability, including headers, trailers, electronic signature, encryption and ability to exchange data not only with regulatory authorities, but also licence partners, CROs and other third parties.

The next step is to prepare an implementation plan. The European guidelines include template plans7 ( which essentially address the following aspects:

  • Evaluate and address deficiencies in current system capability
  • Set timeframes for testing and start of regular electronic transmission of ICSRs
  • Determine methods of communication with other parties
  • Map of data items
  • Define approach to upload/download of case safety reports
  • Select gateway product for interface with the EMEA/FDA
  • Determine management procedure for followups and duplicates
  • Implement MedDRA.

Once the implementation plan is finalised it can be sent, together with a “Declaration of Intent” to the EMEA/National Authority(ies). Once digital certification for Internet communication has been obtained you can exchange test data with the EMEA and National Authorities including acknowledgement of receipt. Throughout the entire submission process an audit trail needs to be maintained including uploading the file, sending the file, through to receiving message receipt and ICSR acknowledgements.

A solution for smaller companies without the appropriate internal resource or infrastructure is to outsource their pharmacovigilance operations to a Contract Research Organisation -a subject for a paper in its own right.


In conclusion -are we ready for paperless pharmacovigilance?Successfulelectronictransmission of information relies on the definition of common data elements and standard transmission procedures.1 However, until electronic reporting becomes mandatory it is unlikely that all companies will participate; until all companies participate in a common process the possible efficiencies will not be realized. It is interesting to note that of around 3,500 companies in Europe that the EMEA has identified that will need to report SAEs electronically, only around 20 have performed any testing to date.

The January 2003 deadline is fast approaching and there is still a lot to do. While few companies are totally ready for e-submissions, many are making plans. However, it is believed that the majority are either at the start of this activity or have ignored it to date. The EMEA may not expect total compliance on Febrary 1, 2003, but does expect plans to be in place at that time and for an increasing proportion of companies to come “on stream” during 2003. The question the reader must answer is – “as a pler in this process, is your company ready?”


  1. Maintenance of the ECH Guideline on Clinical Safety Data Management including the Maintenance of the Electronic Transmission of Indiviual Case Safety Reports Message Specification (ICH ICSR DTD Version 2.1).
  2. ICH M2 Recommendations on Electronic Transmission of Individual Case Safety Reports Message Specification.
  3. Commision Directive 2000/83/EC (an update of Directive 75/319/EC).
  4. Council Regulation (EEC) No. 2309/93, articles 24 and 51, paragraph c.
  5. CPMP/PhVWP/108/99 Notice to Marketing Authorisation Holders Pharmacovigilance Guidelines (January 1999).
  6. EMEA/H/31387/01/FINAL Note for Guidance Regulatory Electronic Transmission of Individual Case Safety Reports (ICSRs) in Pharmacovigilance March 1, 2002.
  7. CPMP/PhVWP/2058/99 rev 1 Joint Pharmacovigilance Plan for the Implementation of the ICH E2B, M1 and M2 requirements releated to the electronic transmission of Individual Case Safety Reports in the Community.
  8. Notice to Applicants, Volume 9, Part III – EU Electronic Exchange of Pharmacovigilance Information
  9. CDS018/CDERGUID/4153DFTFDA Guidance for Industry – Providing Regulatory Submissions in Electronic Format – Postmarketing Expedited Safety Reports (excludes vaccines).
  10. EudraVigilance: the new Pharmacovigilance System in the European Union, brochure at
  11. Evaluation of the Status of the Implementation of teh Electronic Transmission of Individual Case Safety Reports for Medicinal Products for Human Use Authorised in the European Union in accordance with the Centralised, Mutual Recognition and National Procedure.
  12. Fedreal Health Insurance Portability and Accountability Act of 1996.