Coinciding with LORENZ’s 20th anniversary, the German BfArM now accepts electronic submissions and, in doing so, will save several million pages of paper each year.
On March 26th, 2010 the Federal Institute for Drugs and Medical Devices (BfArM) announced that as of 31st March, sponsors may submit their drug applications in eCTD format (electronic Common Technical Document) or NeeS (Non eCTD electronic Submission) format. According to the CMD(h) guidelines the only documents which still need to be submitted on paper and with a written signature are the cover letter, the application form in Module 1.2, the reviewer’s explanations document in Module 1.4 and a cover note. This will save BfArM and, in particular, the sponsors a great deal of time and money in the application process. (A sample calculation of a pharmaceutical company in Berlin can be found below.)
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Background: LORENZ Archiv-Systeme GmbH has been supporting the BfArM and other European Authorities in developing concepts and specifications for the submission of electronic applications and their approval since 1989. LORENZ assisted in the process of devising the very first international specification format under the name of DAMOS (Dossier Application Methodology On Optical Storage) in Europe and technically implemented the transition from CTD to the current application of the eCTD format using the LORENZ docuBridge® software. |
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LORENZ docuBridge® is the worldwide leading software in the compilation and review of electronic submissions for the authorization of medical and pharmaceutical products in this niche market of submission management. There are approximately 30 suppliers worldwide that offer software tools for the compilation of electronic submissions to the pharmaceutical and regulatory industries. One of the unique features of the BfArM/LORENZ partnership is the implementation of a software solution which can be used both by industry, to the complete process of compilation and also by the authorities, to review submissions. All 180 installations around the world of LORENZ docuBridge® software contain the same software code, which simplifies the process of updating the software and maintaining it to conform to the required standards.
Implementation within the Federal Institute for Drugs and Medical Devices (BfArM):
The BfArM employees have been working with LORENZ software products since the introduction of the DAMOS Standard in 1993. Initially the software PharmBridge Review was used at single work stations to scan and later to submit documents for approval (onto magneto-optical discs and later CDs). In 2000 LORENZ docuBridge® was introduced as a network-compatible solution for the central eSubmission review of DAMOS submissions and eCTDs. Additionally, scanned paper dossiers (EDA CDs) have been managed in LORENZ docuBridge® for the past 15 years by BfArM. BfArM was the first regulatory authority worldwide to process and manage submissions in the NeeS format within the same system using the same functions.
Today LORENZ docuBridge® is available for practically every reviewer within BfArM. The documents that have been submitted on CD for approval are checked-in and validated for specification conformity with the BfArM eValidator (developed by LORENZ) by a central BfArM department. After the submission has passed technical validation and has been cleared for assessment, the submission is transferred to LORENZ docuBridge®. Due to the modern client/server architecture and the ability of all employees to access the system, approval and review are carried out more efficiently and eliminate a lot of the red tape formalities which would otherwise slow down the drug application process. In order to give all sponsors the chance to validate their own eCTD or NeeS submissions prior to submitting, BfArM together with LORENZ offers the eValidator as a free software download from the BfArM homepage (www.bfarm.de/BfArM-eValidator.zip).
Additional fields of application:
As a central submission and document management system, LORENZ docuBridge® is linked to the AMIS system, the product-database of the BfArM. The reviewer not only has access to the current eCTD submission during processing but is also able to access all submission-related documents, such as product information labels, at the same time. Another process supports the automatic exportation of documents from LORENZ docuBridge® into the public domain of AMIS, which allows the pharmaceutical company, the so-called sponsor, direct access to these documents. The LORENZ docuBridge® submission viewer is used for reviewing all submitted eCTDs. This offers an array of functionalities and provides the reviewer with optimal support. This includes the simple navigation via an electronic table of contents as well as the use of hyperlinks and bookmarks. The system also has the capability to compile notes and personal hyperlinks to provide an efficient workflow for several reviewers within one system environment. The constant availability of a central system with additional options such as copy and paste directly from within the submission document considerably reduces the working volume for the reviewer. In the long run this results in improved communication with the sponsors and faster processing of the application.
Additional benefits of the international specification standards eCTD:
The eCTD-related specifications, which are based on XML (extended mark-up language), provide the guidelines for document transportation in various formats (ADOBE PDF, Microsoft Word, etc...). They also specify the so-called lifecycle management of these files (one complete document based on several single files). Lifecycle management has been implemented in LORENZ docuBridge® and also allows for the lifecycle of a submission to be tracked over a range of several versions. Submissions which have been imported by the BfArM are available to reviewers in the software’s archive. Subsequent sequences of submissions can be added to existing sequences to continue the lifecycle. This process is extremely important for long term archiving in the industry in general. From a legal aspec, comprehensive documents must be stored and maintained for at least 40 years. The pharmaceutical company is also obliged to update all documents with the authorities at regular intervals. More than 4.5 million pages of submission documents are received by BfArM each year. This is a vast amount of paper, which is delivered by lorries, placed in storage by pallet stackers and subsequently unpacked by hand and distributed to various departments. Electronic submissions represent an immense savings potential, not only in CO2.
A calculation from the Ministry of the Environment: 100,000 pages represent one ton of CO2! After cooperating for more than 20 years in the field of electronic submission with BfArM, we are delighted that this important step towards electronic submissions has been taken.
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Timeline - Cooperation BfArM |
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| 1989: | Presentation of the first software draft and initial contract for the compilation of Electronic Document Software (EDS) |
| 1989: | Working group CUZA (Computer Supported Application for Admission) comes into force |
| 1990: | Cooperation in the follow-up organisation "The DAMOS Group" |
| 1992: | Development of PharmBridge Review |
| 1993: | First implementation of PharmBridge Review at BfArM |
| 1993: | Further development of DAMOS standards and expansion of DAMOS workstations in BfArM to more than 80. An additional 17 European agencies accept the standards that have been set. Introduction of the regulatory groups IRF, (International Reviewer Forum) and the DAMOS working group in BfArM with participation from the industry, who contribute to the overall success with their own productivity results, i.e. indexation requirements for electronic submission documents (Dr. Jörg Lekschas, 1995) |
| 1998: | Cooperation in the follow-up organisation "ICH M2, CTD, eCTD“, MANSEV project of the EU |
| 1999: | Implementation of the eCTD import/export function in docuBridge® (EU, North America, and Japan) |
| 2000: | Pilot implementation of LORENZ docuBridge® as a multi-user system for electronic submissions |
| 2001: | Implementation of interface for product database AMIS at BfArM |
| 2002: | Introduction of productive system LORENZ docuBridge® at BfArM |
| 2004: | Implementation of NeeS submissions (specified by EU - technical implementation group) in LORENZ docuBridge® |
| 2008: | Administration of sample documents in LORENZ docuBridge® |
| 2009: | Administration of PSURs in LORENZ docuBridge® |
| 2010: | Electronic submission in accordance with eCTD specification and NeeS guidelines |
Based on the following historical ROI calculation, it is possible to calculate the potential savings to the pharmaceutical industry by migrating to electronic submissions:
Production costs for scientific documentation in the field of drug submission for the pharmaceutical industry. May 18th, 2004 Based on a study conducted by a LORENZ Service Unit in Berlin, it was established that one of its clients, Berlin-Chemie (BC), accumulated an electronic archive of 3.2 million pages of submission related documentation between 1995 and 2003. The document archive which was directly administered by BC has not been taken into account. This means that the actual number of pages would actually be higher. The digital archive contained all the paper-based submissions which had been compiled for the regulators. BC provided 32 agencies with submission documents. Several sets of documentation had to be submitted to the agency, on average three copies of any one submission was required. As not all products were sent to every agency and not all agencies required three copies, the number of pages for BC has been calculated at a lower rate, reduced to 10 agencies.
Page calculation:
3.2 million pages X 10 agencies X 3 copies for BC = 96 million pages. The following average value for a production price of 3 € per page has been established for invoices which have been billed to BC and other companies during the past few years, but also from sample calculations from drug companies for: compilation, processing, administration, organizing, filing/archiving, publishing, transportation. (The actual price would realistically be around € 5.00 per page, as processing demands a great deal of manual labor).
Cost calculation per page:
96 million pages x € 3 amounts to a production handling cost of 288 million Euros for BC. What was the impact of this here in Germany? In 2004, approximately 600 relevant pharmaceutical companies of varying sizes were registered in Germany. BC belongs in the top third, but we were conservatively acting on the assumption of 100 companies.
Price calculation for Germany’s drug companies: production and handling
100 companies X production handling costs of € 288 million = € 28.8 billion In other words – based on this survey for the years 1995 to 2003, € 28.8 billion (€ 3.6 billion annually) had been invested by the industry in Germany alone for the production of scientific documentation in the field of drug approval processing in the pharmaceutical industry. As previously indicated, BC is responsible for 32 regulatory agencies that also process these documents, i.e. compilation, process-sing, administration, organizing, archiving, publishing, and transportation. This has not been included in the calculation. Note: The present day technology of LORENZ docuBridge® permits electronic documentation communication between applicant and regulatory agency.
Even if the accumulation of documents is only reduced by 30% when applying LORENZ docuBridge® a cost saving potential of several billion Euros can be achieved!
Conclusion:
In our example of Berlin-Chemie with 96 million pages x 3 € = € 288 million / 8 years = €36 million / 30% reduction equivalent to a savings potential of €10.8 million annually, providing that electronic processing was consistently introduced – in contrast a relatively low investment for LORENZ docuBridge® and services. It would certainly be very interesting to conduct a European or global comparison ...