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Frequently asked questionsFrequently asked questions are detailed below. We try to ensure that all information provided on this website is correct at the time of inclusion but we do not guarantee the accuracy of such information. Please email our webmaster if you have any comments, queries or corrections. What can my organisation do now to prepare for future eCTDs? Who is responsible for the specification for the eCTD? Where can I find the specification for the eCTD? Where can I find information on the use of eCTD in the EU centralised procedure? Where can I find information on national requirements for eCTD in European Union countries? What tools are needed to review eCTDs? When will eCTD submissions be accepted without simultaneous submission of paper CTDs? What is a document management system? Do I need to know about XML in order to build an eCTD? What is the difference between PIM and SPL? Note: Text from this website was used with the permission of iRegulatory Ltd in the EMEA document on Questions and Answers relating to Strategic and General Aspects of eCTD Implementation (EMEA/596870/2007). What is an eCTD?The electronic Common Technical Document (eCTD) is the electronic equivalent of the Common Technical Document (CTD), which is a standard format for submissions to the authorities and agencies responsible for regulation of pharmaceutical products in the USA, Europe and Japan. What can my organisation do now to prepare for future eCTDs?Even if your organisation has no firm plans to generate eCTD submissions in the near future, there are important steps that can be taken now to prepare for the future. Some of these steps can provide tangible benefits when it comes to generating paper CTD submissions. The following steps should be considered: Review internal processes for electronic authoring of documentsThe way that documents are authored can significantly affect the amount of work that is needed at the time of publishing. If documents are authored in MS Word using templates with styles, bookmarks and electronic cross-referencing, then PDF files generated from these files will be automatically bookmarked and hyperlinked internally. This saves on the amount of manual hyperlinking that has to be done at the time of publishing. The use of suitable electronic templates guarantees a consistent typographical style and improves the accuracy and quality of cross-referencing. It also allows cross-referencing to be inserted at the time of writing and not left until the end of the process. Review internal arrangements for electronic archiving of documentsThe creation of a centralised secure electronic repository (preferably a document management system) for electronic source documentation is recommended (together with appropriate internal processes, procedures and workflow), in order to ensure that electronic source documentation is readily available and that documents can be verified as being authentic electronic versions of the corresponding documents stored in the paper archive. Ensure that electronic source documentation will be available from third parties e.g. licensing partners and CROs.The availability of electronic source documentation is important for assembly of an eCTD. It is recommended that negotiations with licensing partners and CROs should include discussion of availability of electronic source documentation in a suitable format for future electronic regulatory submissions. Who is responsible for the specification for the eCTD?The main specification for the eCTD was developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Specifications for eCTD Module 1 (regional information) have been produced by EMEA (for Europe) and FDA (for the United States). Where can I find the specifications for the eCTD?Please follow the links below for specifications: Main eCTD specification (v3.2) Module 1 specification for the European Union Regional specifications for the United States Regional specifications for Canada Where can I find information on the use of eCTD in the EU centralised procedure?The EMEA website provides information on principles and practices for the use of eCTD in the centralised procedure. Where can I find information on the use of eCTD in the EU mutual recognition and decentralised procedures?CMD(h) (the Co-ordination Group for Mutual Recognition and Decentralised Procedures - Human) has issued a best practice document which sets out principles and practices for the use of eCTD in the EU mutual recognition and decentralised procedures. Where can I find information on national requirements for eCTD in European Union countries?With great difficulty! Information in Chapter 7 of the Notice to Applicants is generally inadequate, and the websites of individual European agencies (see Heads of Agencies website for links) do not always provide information regarding requirements for electronic submissions. The EMEA website provides useful links to individual agencies that do provide guidance on their websites. How are eCTDs built?An eCTD can be built manually (not recommended) or automatically, using integrated document management and publishing software. Such solutions are available commercially from numerous vendors (see our vendor links page). What tools are needed to review eCTDs?An eCTD can be viewed on a computer running a standard web browser such as Microsoft Internet Explorer or Firefox, with Adobe Acrobat reader installed. Most computers will have suitable web browser software pre-installed, and Acrobat Reader is available as a free download from Adobe Systems Inc. Notwithstanding this, specialist reviewing tools are really important, because the aforementioned standard tools are inadequate for viewing the successive changes to an eCTD that are likely to occur during the lifecycle of a product. Reviewing tools are available commercially from numerous vendors (see our vendor links page). Free reviewing tools are available from Rosetta and ING Group. When will eCTD submissions be accepted without simultaneous submission of paper CTDs?In the United States, eCTD is the mandatory electronic format for new submissions, although it is still possible to file paper submissions. The FDA will only accept eCTD submissions from companies that have demonstrated adequate technical competence in eCTD compilation, as established by FDA testing of a sample eCTD submission. In Europe, since 1 July 2008, the EMEA has accepted eCTD submissions without the need to submit paper, although this change had little impact, initially because almost all CHMP members still required paper submissions when they were acting as rapporteur or co-rapporteur. From 31 December 2008, CHMP members are supposed not to be able to request paper copies, although it remains to be seen whether everybody will act in the spirit of the EMEA's letter of intent. Further information is available on the EMEA website. With regard to EU national agencies, a target date of end 2009 was adopted at the European Heads of Agencies meeting in Reykjavik, Iceland, held on 23rd - 24th February 2005. Four years on, only a few of the European national competent authorities are accepting eCTD with no requirement for paper (including Belgium, Netherlands and the United Kingdom), with less than a year to go before the deadline. Barriers to the uptake of eCTD in Europe have included the lack of a legal basis for eCTD, legal requirements for a paper copy as the "official" archive copy in many EU countries and budgetary constraints on investment in the necessary IT infrastructure. The situation in Europe is further confused by the lack of a central information source on eCTD readiness of individual countries. Information in the Notice to Applicants is generally inadequate, and the websites of individual agencies do not always provide information regarding requirements for electronic submissions. The EMEA website provides useful links to individual agencies that do provide guidance on their websites. What is a document management system?A document management system is an electronic storage repository for documents, with sophisticated access control and version control. Documents are "checked in" and "checked out" so that only one user can work on a document at a time, eliminating problems with multiple versions. The system can be configured to retain superseded versions and keep an automatic record (audit trail) of who has checked the documents in and out and when. Integrated document management and publishing solutions for CTDs and eCTDs are available commercially from numerous vendors (see our vendor links page). What is a publishing engine?A publishing engine is software that automatically generates a dossier from a set of individual electronic files. In the case of a typical paper-based CTD, the publishing engine divides the submission into appropriately sized volumes, adds page numbers, headers and footers if required, resolves cross-references and inserts tables of contents and cover sheets at the beginning of each volume. The output is a typically a collection of PDF files, one for each volume, that can be printed, copied and assembled in the usual way. In the case of an eCTD, the publishing engine creates the eCTD directory structure and populates it with PDF files, resolves hyperlinks, calculates MD-5 checksums and creates the XML backbone automatically. The output is a complete eCTD which can be copied to a CD-ROM. Integrated document management and publishing solutions for CTDs and eCTDs are available commercially from numerous vendors (see our vendor links page). What is PDF?PDF is "portable document format", a proprietary file format for documents developed by Adobe Systems Inc. The viewer software for PDF (Acrobat Reader) is distributed free by Adobe, and there are versions for all operating systems is common use. Thus, documents distributed in PDF can be read by anybody, irrespective of the type of computer that they use or their operating system. The PDF format is also relatively compact, which means that download times are reduced. PDF also has useful security features, including support for digital signatures. What is an MD-5 checksum?An MD-5 checksum is a value which is computed from the contents of a file, using a special algorithm. This value is sent along with the file when it is transmitted. The receiving party can repeat the checksum calculation and compare the value obtained with the one sent with the file. If the two values are the same, the receiving party has a high degree of confidence that the data were received correctly. What is XML?XML is Extensible Markup Language, a powerful and flexible means of storing structured information. An XML file is a simple text file, that contains text in a structured format. Do I need to know about XML in order to build an eCTD?No. A number of vendors provide electronic publishing software that generates the XML backbone automatically. Integrated document management and publishing solutions are available available commercially from numerous vendors (see our vendor links page). These tools provide intuitive graphical environments for working with eCTDs, and the XML processing is done automatically "under the hood". Thus there is no need for the users to have any specific knowledge of XML. What is a NEES submission?NEES stands for "non-eCTD electronic submission". A NEES submission is essentially an eCTD without any XML backbones. In a NEES submission, the XML backbone is replaced with hyperlinked Tables of Contents in PDF format (Sections 1.1, 2.1, 3.1, 4.1 and 5.1). These sections are not needed in an eCTD, because the XML backbone functions as a hyperlinked Table of Contents. The XML backbone also includes lifecycle management information that describes how the files being submitted relate to those submitted in previous submissions (sequences). In a NEES submission, the covering letter must include a detailed description of how the files submitted in the current submission relate to what has been submitted previously, since there is no XML backbone containing this information. Guidance on NEES in Europe is available on the EMEA website. In Europe, NEES can be viewed as an alternative to eCTD which is especially valuable for authorised products for which paper submissions have been used previously. In order to use the life cycle management features of eCTD in this situation, a "baseline" eCTD (sequence 0000) is needed; this contains the current, approved documentation set for the product and provides a foundation for future electronic life cycle management. As it can be time-consuming and resource-intensive to prepare this baseline eCTD, NEES is a good alternative in this situation. What is PIM?PIM stands for "product information management", a new XML format for pharmaceutical product information (SPCs, labels, patient information leaflets etc) in Europe that is expected to replace Microsoft Word product information eventually. PIM is still in the testing stage for the EU Centralised Procedure at present. The Data Exchange Standard (the structure of the XML) is still evolving, and the EMEA reviewing system is still under active development. Like eCTD, PIM submissions are made as "sequences" - only changed information is submitted in each sequence, However, unlike eCTD, PIM is "bi-directional" - after the initial submission, agencies will respond with comments and queries in the PIM XML format. The rationale for PIM is best illustrated by giving an example. Product X has two forms (tablet and injection), and three strengths of each i.e. a total of 6 strengths. There is a separate patient information leaflet for each strength, each of which is avalable in 23 European national languages. The total number of individual patient information leafets for Product X is thus 138. If the telephone number of a distributor changed on the last page of the leaflet, then this would necessitate a change to 138 Microsoft Word documents. In contrast, in the PIM format, this information is stored only ONCE and is REFERENCED 138 times, thus making the change much easier to manage. Overall, the reduction in duplication of information with PIM will lead to increased efficiency on both sides (especially in managing the production and review of translations), and lower potential for errors and inconsistencies. PIM also enforces compliance with the QRD templates. PIM represents a step change in how product information is managed in Europe. Pharmaceutical companies wishing to adopt PIM will need to invest in suitable information systems and re-engineer their internal processes and procedures for managing labelling. What is SPL?SPL stands for "structured product labelling", an XML format for pharmaceutical product information in the United States. Submission of product information in SPL format is mandatory in the USA. The rationale for SPL is that it facilitates exchange of information between different health information systems, and provides support for index-based searching (based on coding of terms, in a similar way to adverse event coding e.g. MedDRA). For example, a simple text search for "liver toxicity" in a PDF or Microsoft Word document would miss "hepatotoxicity", "hepatic impairment", "hepatic toxicity" etc. In contrast, an index-based search (based on a coding system) would pick up all relevant references, because synonymous terms are all allocated the same code. The SPL XML format includes coding information to support this type of searching. What is the difference between PIM and SPL?PIM and SPL were designed for completely different purposes (see above), and similarities are restricted to the following::
PIM and SPL have a completely different XML structure. What are Study Tagging Files?Study Tagging Files (STFs) contain additional descriptive information (meta data) on nonclinical and clinical studies in Modules 4 and 5. They are required only in the USA. One STF is provided for each study in Module 4 and 5, placed in the same folder as the files for the study in question. The STFs are referenced in the main eCTD XML backbone (index.xml) file.
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