eAF new MAA

1. eAF new MAA Webinar for the usage of an eAF at NCA level • Presented by: Georg Neuwirther, Klaus Menges and Kristiina Puusaari

2. Agenda Overview and Status of ImplementationSpeaker: Georg Neuwirther (AGES, chair eAF MG) Processing the eAF for initial applicationSpeaker: Kristiina Puusaari (EMA), Klaus Menges (BfArM) Questions and Discussion

3. Overview and Status of Implementation

4. eAF Maintenance Group (eAF MG) • Group of business and IT-experts from NCAs, EMA and Industry • eAF MG is in charge of implementing the eAF according to the eSubmission Roadmap • Evolution: 1. word AF -- 2. eAF –- 3. Single Submission Portal • Please contact us via eaf@ema.europa.eu for any questions!

5. (reflecting final adopted version 1.0 dated 07/11/14) • Ongoing/optional • Mandatory Background eSubmission Roadmap • NCA & industry survey • eSub Roadmap Adoption • draft eSub Roadmap • Use of eCTD v.4 • All submissions in CP, DCP and MRP (human) in eCTD • All submissions in CP (human) in eCTD • Use of NeeS and eCTD in DCP and MRP (human) New MAA in DCP (human) in eCTD • New MAA in DCP and MRP (human) in eCTD • All submissions in MRP (human) • All other MRP submissions (human) • Use of VNeeS in CP, DCP and MRP (vet) • All submissions in CP, DCP and MRP (vet) in VNeeS New MAA in CP and DCP (vet) in VNeeS • All other in CP and all MRP submissions (vet) • eGateway (CP, human) • Single Submission Portal with integration of eAF • for all submissions (human and vet) • eGateway (CP) • (human and vet) Single submission portal - combined CESP/Gateway in CP (human) • CESP (human and vet) • Single submission portal - combined CESP/Gateway • in all other procedures (human and vet) • Use of eAF in all procedures (human and vet) • in CP • eAF in all procedures (human and vet) • in all other procedures • NCA use of Common Repository for CP submissions (human) • NCA use of Common Repository for all CP submissions • (human) • Use of PSUR Repository for CAPs and NAPs (human) • Use of PSUR Repository for all CAPs and NAPs • (human) • 2013 2014 2015 2016 2017 2018 eSubmission Roadmap Timelines

6. Successful start of compulsory usage of the eAF for Centralised Procedures (all types, human&veterinary). Transitional period ended on the 1st of September; applicants are be requested to resubmit using eAF only if other formats are received (scanned eAF/ word)! Status eAF usage in CP • CESP (human & vet) • Single submission portal - combined CESP/Gateway • Fully functional • single submission portal for all submissions (human & vet) • eGateway (CP) • (human and vet) • eGateway (CP, human) • (Mandatory for CP-human, optional for other procedures) • Use of eAF • in CP • eAF in all procedures • in MRP/DCP • 2013 2014 2015 2016 2017 2018

7. Where to find eAFs? Option 1 - link to eAF webpage from Eudralex page Notice to Applicants (European Commission) http://ec.europa.eu/health/documents/eudralex/vol-2 http://ec.europa.eu/health/documents/eudralex/vol-6/index_en.htm Option 2 eSubmission Homepage (EMA) http://esubmission.ema.europa.eu/eaf/index.html

8. Release Plan of eAFs Release Plan published here: http://esubmission.ema.europa.eu/eaf/index.html Excerpt of Release Plan (status 29.10.2015)

9. Important Documents

10. National translations of the eAF eAF-MG was asked by a member state to provide translations of the eAF Conclusion after discussion in the eAF-MG and after consultation of the chair and co-chair of ITDEC1) The eAF-MG has only the mandate to provide the existing application forms in the new PDF-technology, in English 2) The eAF-MG has to follow the endorsed eSubmission Roadmap

11. What to do at NCAs level (key steps)? • Check IT infrastructure (Adobe Version 10 or above) • Ensure compatibility of business systems with EUTCT terms • Check connectivity to EUTCT (search for substances) • Update internal guidelines and offer internal trainings • Same content new functionality • Implement automated data import • Pilots in AT, DE, IT, .. eaf@ema.europa.eu

12. eAF support structure • Impact of mandatory use • Receipt and validation • What to do in case of issues • Locking the form and signatures • How to check whether eAF is locked • Navigation and blocks/context (grey border) • Check eAF compliance • Controlled terminology and Term Request Process • Workarounds • Form validation • Areas, which might cause difficulties when extracting data: Closure, container, material … • XML contains invisible data (CR for 1.20) Processing the eAF for Initial application

13. eAF- Support Structure • Effective support for applicants & NCAs/EMA will be a key success factor during the implementation phase of mandatory use of the eAF for all EU procedures! • Why will support be needed? • Technical change from Word to PDF format • eAF structure cannot be changed by the applicant like Word forms • Majority of free text fields have been replaced by controlled vocabularies – terms are selected from EUTCT-catalogues – if terms are no available they should be requested through MDMS new term request process • Paper form was an isolated document with no direct IT-integration into the business process (e.g. for automatic data import). Now eAF data will be used directly in IT-systems reducing manual workload and human error

14. eAF- Support Structure • Technical questions, comments, change requests – forward the applicants/MAHs to eAF@ema.europa.eu • Procedural questions • CP – eAF@ema.europa.eu • MRP/DCP/NP– if questions are received by EMA the applicant is advised to contact the RMS/relevant NCA • Mixed queries containing both technical and procedural queries received directly by RMS/NCA – RMS/NCA can forward the reply to eAF@ema.europa.eu and EMA will complete response with the technical details and will reply to the applicant with NCA in copy • Mixed queries containing both technical and procedural queries received by EMA – EMA will reply to the user providing response on the technical issue and will direct the applicant to RMS/NCA for the procedure aspects • In case the RMS/NCA is not sure of the reply they can always forward the queries to eAF@ema.europa.eu

15. eAF- Support Structure • (no big differences to the AS-IS-situation)

16. eAF – Impact of mandatory use • Impact on NCA staff Preparation • Please remind applicants during pipeline/pre-submission meetings on the upcoming mandatory use for all MRP/DCP/NP applications • If you receive queries from applicants/MAHs regarding variations and renewals, please remind them of the mandatory use. You can provide them a link to eAF document introducing the mandatory use published on the eSubmission website • Remind applicants that the eAFs should be submitted as ‘real’ eAFs – meaning that they are kept in electronic format and are submitted with the xml. Forms that have been printed and scanned as PDF lose all their intelligent features and become flat PDFs. These do not allow import/export of xml data into receiving systems • Remind applicants/MAHs that there is no further transitional period regarding the usage – the forms are already available from the eAF website

17. eAF – Impact of mandatory use • Impact on NCA staff Preparation • The mandatory use of the eAFs does not change any existing wet signature requirements by the NCAs – only the form changes – i.e. instead of the word or pdf version of the AF available in the NTA Eudralex website the only forms available are the PDF eAFs • These PDF eAFs can be read just like any other PDF document and receiving them doesn’t require special tools at the NCAs – Adobe v.10 is the only requirement

18. eAF – Receipt and validation • All applications received after 1 January 2016 should be received in eAF format • You can recognise the eAFs easily as they look different from the NTA paper forms, see example below of : • the Initial H-MAA: • eAF Paper form

19. eAF – Receipt and validation Note: The error in the European Commission header for the initial V-MAA eAF has been noticed and will be updated in the next release of the eAF. • the Initial V-MAA: • eAF Paper form

20. eAF – What to do in case of issues/problems • If you cannot open the eAF – contact your IT service desk as soon as possible to confirm you have the correct version of Adobe installed in your PC. • If you cannot see all fields in the eAF – see example of the same form displayed differently depending on the PC settings below – please contact your IT service desk as soon as possible to have the correct version of Adobe installed on your PC. • Issue with Adobe/EURS or browser plug-in eAF with correct PC set up

21. eAF – locking of the form and signatures • If you have received an eAF that has been filled, printed, signed and scanned as PDF you should inform the applicant and inform them that it is very important to use the eAF correctly i.e. sign the form electronically and not as a ‘flat PDF’ – information from flat PDFs cannot be uploaded to your receiving systems. • How to recognise if the form has been saved as ‘real eAF’ or if it is a scanned copy of the eAF? • The text in the ‘real eAF’ is greyed out • The ‘Form validation’ page is present in the form (the last page) (see below) • At the bottom of the ‘Form validation’ page you are able to save form, print form, export XML and update lists but all other buttons have been disabled • If the form hasn’t been ‘locked’ by the applicant and you are able to make changes to the form, you should inform the applicant to ensure they lock the form in future to prevent regulators making unintentional changes

22. In process once the signature image has been added eAF – locking of the form and signatures • Once the form has been saved and was locked • The image could be an image of a real signature as well

23. locked • unlocked Navigation

24. Identification of entered data • Proposed to used bolded text or grey background for data fields

25. eAF – controlled terminology • The dropdown lists or selections from catalogues include terms according to standardised nomenclatures and quality standards for medicinal substances and products of EDQM or the EUTCT system • In case of a missing term – as a general rule – in order to complete an eAF, please use the eAF Term Request Form. Once completed, you will need to submit your form via email to mdms@ema.europa.eu • A provisional term may be added to the list within 5 working days; however, please note that there is a possibility that the term might not be approved and ultimately added to the list for future use. For further guidance please refer to http://esubmission.ema.europa.eu/eaf/5_eAF%20Term%20Request%20Process.ppt • In case NCAs identify an inappropriate term used the applicant must correct it and should ask for a provisional term according to the defined process

26. eAF Term Request Process • In case MAH/NCA will ask for new terms •  EMA provides a standardised request procedure available on the eAF website • * In the term request form there are detailed instructions on what information is required to apply for changes in each list.

27. eAF Term Request Process – 5 days SLA

28. eAF – workaround solutions • The most commonly used workaround solution used by the applicants/MAHs would be an addition of an annex to the form as the relevant section cannot be filled as required in the eAF - these are not the annexes as referred to in section 5 of the initial forms • The annex must be included as a separate, clearly named document in the same folder (e.g. 1.2 in EU M1) where the application form is provided! We recommend that the annex is named as per the section of the form that is provided in the annex. • The standard PDF functionality of adding an annex using the paperclip function must not be used as the annexed documents will not be visible when viewed via eCTD review tool (e.g. EURS)

29. eAF – workaround solutions • Detailed instructions how to use workaround solutions is available in the eAF Q&A document and the eAF Technical Guidance documents – both are published on the eAF webpage – you can always refer the applicants to these documents and if they need more advice refer them to eAF@ema.europa.eu • If you (repeatedly) receive a question that is not responded to in the guidance documents, please provide the question and the relevant response to eAF@ema.europa.eu with title ‘New question to be addressed in the eAF guidance’ and we can add the question in the Q&A document and add additional guidance in the eAF Technical Guidance document during the next update of that document • The forms have been built so that they contain build in business rules, guiding the applicants to fill in the forms the correct way and this might in some sections compromise flexibility, however, the forms remain flexible and there are multiple different ways to fill in several sections depending on each specific application. EMA directs MAHs to NCAs/RMS when there are questions on how to fill in certain parts of the forms for MRP/DCP/NP applications to ensure there are no content validation issues

30. eAF – form validation • All eAFs contain built in business validation based on complex validation rules – occasionally NCAs identify that some business rules related to MRP/DCP are not correct and should be changed – in these cases please report to eAF@ema.europa.eu as soon as possible to raise a change request • Ideally, all validation errors are solved before finalising and locking the form – remind applicants it’s very important to save the unlocked forms before closing them in case there are any validation issues and updated form is requested – it is not possible to change already locked forms and in case no unlocked version has been saved the applicant might have to refill the whole form in order to make changes to meet the validation comments • Occasionally it is not possible to solve all validation comments and once the forms are locked the form will display the number of ‘form validation errors’ at the very end of the form – however it is not possible to see to which sections these validation errors refer to. Validation errors in the form can, in most cases, be ignored as often refer to sections for which the applicant has provided an annex for.

31. eAF – form validation • The form validation is not a technical eCTD or NeeS validation • Leaving validation errors in the form does not affect eCTD or NeeS validation - the purpose of this validation is simply to guide the applicants to fill in the form correctly and to fill in mandatory fields of the forms • In many cases, form validation errors do not lead business validation errors • Form that doesn’t have any form validation errors might still be invalidated during the business validation step – it’s important not to confuse form validation with business content validation! • If a new version of the forms has become available / entered into force between the receipt of the application and request for supplementary information (validation comments) the applicant doesn’t need to change the form version (unless this has been the case in the past with paper forms)

32. CTLs for containers, closures, devices • Short lists of controlled terms might raise problems to describe the item precisely • Missing term list requires additional quality checks and causes additional workload • 145 national terms registered

33. CTLs for containers, closures, devices • 17 terms in EUTCT versus 45 national terms • 38 terms in EUTCT versus 220 national terms • 32 terms in EUTCT versus 190 national terms

34. XML seem to contain invisible data • Especially in section “1. Type of Application” data entered in the form will remain visible when the corresponding fields are un-ticked, e.g. you added data for a centralised procedure, but un-tick the button to switch to data entry for mutual recognition procedure. To reduce the risk of accidental data loss it was decided to ensure sections completed then hidden would persist. Data may only be deleted on a field by field basis by users. • Concern was raised that these hidden data could be processed in case of automation or when extracted manually. • It seems that these “hidden data” will not be processed as the corresponding root xml value is set to 0, in that case for CP, and details in the data fields below will be ignored. • If the analysis is wrong, unwanted data usage need to be blocked definitely.

35. XML seem to contain invisible data • This „0“ will switch off use of data. In the unlocked form, the data can still be used in case of intentional re-thinking your decision. • It does not matter whether data entered in the below XML elements in case of processing.

36. What to do atNCAs level (key steps)? • Check IT infrastructure (Adobe Version 10 or above) • Ensure compatibility of business systems with EUTCT terms • Offer internal trainings • Same content – different functionality • Update internal guidelines! • Check connectivity to EUTCT (search for substances)Not needed if you only read eAFs • Implement automated data import • like AT, DE, IT, .. eaf@ema.europa.eu

37. Contact Please send any questions to eaf@ema.europa.eu or the responsible NCA contact