Standard operating procedure Title: Processing of type II variations for medicinal products for veterinary use Status: PUBLIC Document no.: SOP/V/4004 Lead author Approver Effective date: 10-DEC-15 Name: Anne-Christine Lantin Name: David Mackay Review date: 10-DEC-18 Signature: on file Signature: on file Supersedes: SOP/V/4004 (16-MAY-08) Date: 04-DEC-15 Date: 04-DEC-15 TrackWise record no.: 3211 1. Purpose This SOP describes the procedure to be followed for the handling of type II variations for centrally authorised medicinal products for veterinary use for which a 30-day, 60-day or 90-day procedure applies. It also applies to variations submitted as a group where at least one of the applications in the group is a type II variation, and where no extension is included as part of the group. 2. Scope This SOP applies to staff in the Veterinary Medicines Department of the Veterinary Medicines Division. 3. Responsibilities It is the responsibility of the Head of Veterinary Medicines to ensure that this procedure is adhered to within their own department. The responsibility for the execution of a particular part of this procedure is identified in the right-hand column of section 9. 4. Changes since last revision Major revision of SOP to take into account the Variations Regulation (Commission Regulation (EC) No 1234/2008) as amended; as well as organisational and structural changes at the European Medicines Agency. 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.
5. Documents needed for this SOP Model letters and document templates for this procedure are available in SIAMED. Validation checklist (EMA/720947/2015) Fee workflow template (EMA/461339/2014) 6. Related documents 98/C 229/03 Commission communication on the Community marketing authorisation procedures for medicinal products Commission Regulation (EC) No. 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products 2013/C 223/01 Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No. 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures Guideline on the Categorisation of Extension Applications (EA) versus Variations Applications (V), NTA, Volume 6C, October 2003 The linguistic review process of product information in the centralised procedure veterinary (EMA/288844/2009 Rev. 4) electronic Application Form (eaf) for variations 1 Dossier requirements for submission of marketing authorisation and maximum residue limit applications (EMA/466102/2007) Centralised procedure - Recommended submission dates (EMA/641657/2014) Guideline on Active Substance Master File Procedure (EMEA/CVMP/134/02) QRD product information templates for veterinary medicines (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listi ng_000185.jsp&murl=menus/regulations/regulations.jsp&mid=wc0b01ac058002d9b0) User guide on how to generate PDF versions of the product information veterinary (EMA/793983/2010) e-submission website (http://esubmission.ema.europa.eu/tiges/vetesub.htm) SOP/PDM/1004 Core master files of medicinal products for human and veterinary use following the centralised procedure SOP/V/4038 Updating of the European Public Assessment Report for a veterinary medicinal product WIN/EMA/0098 QRD forms 2 (former Linguistic Check Forms) 1 The use of the eaf is mandatory from 1 July 2015 in the centralised procedure (Human and Veterinary), and from 1 January 2016 in all EU procedures (Human and Veterinary) SOP/V/4004 10-DEC-15 Page 2/17
WIN/V/4062 - Handling of Veterinary e-submissions 7. Definitions A type II variation is a variation which is not an extension but which may have a significant impact on the quality, safety or efficacy of the veterinary medicinal product concerned. AA APH AR ASMF AWP CVE CVMP DEM DREAM EC EPAR EURS HDep HSer LoQ LoOI MAH PI PM Rapporteur SIAMED SMOP ToA V-VM VAR VROS Administrative Assistant (in VROS) Animal and Public Health service (within V-VM) Assessment report Active Substance Master File Assistant CVMP Antimicrobials Working Party Centralised variation and extension mailbox Committee for Medicinal Products for Veterinary Use Development and Evaluation of Medicines service (within V-VM) Electronic archiving facility/document management system European Commission European Public Assessment Report EXTEDO Universal Review System Head of Department (here: Head of Veterinary Medicines) Head of Service (here: Head of Veterinary Regulatory and Organisational Support) List of questions List of outstanding issues Marketing authorisation holder Product Information Procedure manager appointed for the variation (usually AA in VROS) Project manager (scientific administrator in DEM or APH) CVMP member responsible for assessment of the product Product database and tracking system Summary of opinion Table of actions (CVMP) Veterinary Medicines Department Variation assessment report Veterinary Regulatory and Organisational Support service (within V-VM) SOP/V/4004 10-DEC-15 Page 3/17
Clarification on Commission Decision process: For a variation leading to amendments to the Commission Decision, the EC decision making phase is the same as for a full opinion (without a Standing Committee phase). Only annexes for significant type II variations will be sent immediately to the EC, and the EC decision amending the marketing authorisation will be adopted within 2 months; others (including those also affecting the Annexes) will result in a Commission Decision being adopted within 12 months of the adoption of the opinion and the variation can be implemented as from the date of receipt of the confirmation letter from the EMA. There is no action from the EC when the CVMP adopts a negative opinion. Significant variations are: Variations for the addition of a new therapeutic indication, the modification of an existing therapeutic indication, the addition of a new contraindication, a change in posology, the addition of a non-food producing target species, the modification of an existing non-food producing target species, the replacement or addition of a serotype, strain, antigen, or combination of serotypes, strains or antigens for veterinary vaccine, changes to the active substance of a seasonal, pre-pandemic, pandemic vaccine against human influenza, changes to the withdrawal period for a veterinary medicinal product, a significant animal health or environmental concern. Clarification on timetables for variations: A 60-day timetable is applicable for type II variations. The Agency may reduce this timetable to 30 days depending on the urgency of the matter, i.e. in case of urgent safety-related variations and after agreement with the Rapporteur and CVMP. The timetable may be extended to 90 days for variations concerning changes or additions to the therapeutic indications (to be decided with the rapporteurs). The timetable shall be 90 days for variations concerning: a change to or addition of a non-food producing target species; the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue; the replacement of a strain for a veterinary vaccine against equine influenza. SOP/V/4004 10-DEC-15 Page 4/17
8. Process map(s)/ flow chart(s) SOP/V/4004 10-DEC-15 Page 5/17
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9. Procedure Step Action Responsibility 1.0 Pre-submission 1.1 MAH should send a letter of intent for a type II variation to vet applications mailbox (vet.applications@ema.europa.eu) at least one month, but preferably 3 months, before submitting the application. Check if the co-rapporteur, a peer reviewer and/or AWP need to be involved (normally for significant variations). In that case, CVMP should confirm such involvement at their next meeting. Inform DEM/APH PM about incoming variation, level of required input anticipated and who will be VROS and. Check the date of intended submission against the recommended submission dates. Inform and liaise with the rapporteur (and co-rapporteur, if applicable), VDEM (if the variation concerns changes or additions to the therapeutic indications or concerning a change to or addition of a non-food target species), VAPH (if the variation relates to safety) and confirm to MAH whether submission date is acceptable. If the variation relates to manufacturing issues, check with Compliance & Inspection sector whether inspection is required. NB: If new manufacturers are entered, inform GXP validation Mailbox, giving details. Advise applicant on the correct electronic Variation Application Form to use and to follow guidelines on e-submission. Advise applicant to submit electronic track changes versions of EN product information, if applicable. Proceed to 2.0 2.0 Submission and Validation 2.1 Once type II variation has been received and saved in EURS (and after technical validation done by AA see WIN/V/4062 & WIN/V/4033): Confirm receipt of the application, if requested. Send email to HSer(s),, DEM/APH PM as applicable with link to the application in EURS, mentioning the level of involvment required from PM for significant variations and asking for confirmation of responsible staff, if necessary ( is usually allocated per product). The timetable applicable for the procedure (based on recommended submission dates published on external website) is to be added to this email. SOP/V/4004 10-DEC-15 Page 8/17
Consider if a short team meeting of the VROS and DEM/APH colleagues is necessary before the start of, or during, the procedure (and schedule this meeting, if applicable). Create procedure in SIAMED, allocate resources involved (VROS/DEM/APH PM; ; Rapporteur, Co-Rapporteur, Peer Reviewer, as applicable). Review procedure in SIAMED (4 eyes principle) and save it with status under validation in SIAMED. Create relevant sub-folder in DREAM product folder (under 02 post-authorisation/post activities sub-folder). Generate checklists and validation templates. Check if rapporteur (and co-rapporteur, if appropriate) received application and documentation (written confirmation of receipt of application and date). If variation affects the annexes, save PI under sub-folder 06 translations in DREAM. 2.2 Within 10 working days: Validate the variation according to validation checklist. 2.3 Is the application complete and valid? If yes, go to 2.7 If no, go to 2.4 2.4 Prepare deficiency email listing the issues which prevent validation of the application and send to MAH stating a deadline for response. 2.5 Was the response received on time and is the application considered valid now (see 2.2)? If yes, go to 2.7 If no, go to 2.6 2.6 Send invalidation letter to the MAH stating the reasons for rejection. Copy rapporteurs (and other services in department, as applicable) and financial workflow team (FinancialWorkflow@ema.europa.eu), as an administrative fee will apply. Update SIAMED. Proceed to 8.0 2.7 Finalise validation: For MUMS, confirm the status with the responsible scientific administrator in DEM. For SMEs, confirm the status with the SME office For Scientific Advice, inform the DEM/APH PM, if applicable. Complete the rapporteur s VAR template (and peer reviewer s VAR template, if applicable) with the relevant administrative SOP/V/4004 10-DEC-15 Page 9/17
data. Review validation documents: o Validation letter to applicant including link to recommended submission dates (after endorsement by rapporteur). o Validation e-mail to All Vet CVE including timetable (after endorsement by rapporteur). Send VAR template to rapporteur(s)/peer reviewer. Send Validation email to all CVMP members for information (CVE mailbox; and AWP, if involved). Send validation Eudralink package to the MAH. Copy rapporteur (and co-rapporteur, if applicable). Update SIAMED. Send links to validation letter and cover letter to financial workflow email, if applicable. Proceed to 3.0 3.0 Assessment phase Clock start 3.1 By day 10 (deadline for CVMP members to receive application and documentation): Ensure receipt of acknowledgments of receipt of the variation application package by CVMP members from the MAH. Liaise with applicant if any CVMP member did not acknowledge receipt of the documentation. Save acknowledgement document in DREAM. 3.2 By day 30 or 45 (depending on procedure): Has the rapporteur s VAR been received in accordance with the timetable? If yes, go to 3.4 If no, go to 3.3 3.3 If no report was received by deadline, send a reminder to the rapporteur. Once VAR has been received, proceed to 3.5. 3.4 Check that rapporteur s VAR was sent to the CVMP members (CVE mailbox) and in case report was only sent to Agency, forward the report to the CVE Mailbox. Ensure the AWP secretariat is aware, if applicable. 3.5 Send the rapporteur s VAR by Eudralink to the MAH for information and send outlook invitation to relevant PMs with same deadline as CVMP members to review rapporteur s VAR and provide EMA comments. 3.6 Update Siamed with expected outcome. SOP/V/4004 10-DEC-15 Page 10/17
3.7 In case of a positive recommendation by rapporteur, prepare draft CVMP opinion and draft CVMP AR for first CVMP mailing, where possible. In case of questions, prepare draft LoQ. 3.8 By day 45 or 50 (depending on procedure): Ensure that comments of co-rapporteur were sent by deadline to all CVMP members (CVE mailbox) and in case comments were only sent to Agency/rapporteur, forward them to CVE mailbox. Update SIAMED accordingly. 3.9 Ensure that comments of other CVMP members, EMA (if applicable), AWP and/or peer reviewer, if involved, were sent to all CVMP members (CVE mailbox). 3.10 By day 55/71 (depending on procedure): Has rapporteur s final recommendation been received in accordance with the timetable? If yes, go to 3.12 If no, go to 3.11 3.11 Send reminder to rapporteur. Once final recommendation has been received, proceed to 3.12. 3.12 Send the revised rapporteur s VAR by Eudralink to the MAH for information. Update SIAMED. 3.13 Is a request for additional/supplementary information (LoQ/LoOI) anticipated? If yes, go to 4.0 If no, go to 5.0 4.0 Requests for additional information (Day 60 or 90) 4.1 Prepare LoQ (or LoOI, if responses to LoQ were not totally satisfactory) for CVMP mailing for adoption at the next meeting. Include rapporteur s updated VAR for information. Update the CVMP ToA. NB: As a general rule, a clock-stop of up to 1 month will apply. For clock-stops longer than 1 month the MAH should send a justified request to the Agency for agreement by CVMP. Such requests should be sent after receipt of the Assessment Report, and at the latest before the CVMP meeting at which the request for supplementary information will be adopted. In exceptional cases (e.g. in the case of new indications or where the variation requires an inspection) a clock-stop of up to a maximum of 6 months may be applied. For any follow-on request for supplementary information, an SOP/V/4004 10-DEC-15 Page 11/17
additional clock-stop of up to 1 month will be applied in general; a maximum of 2 months may be applied when justified. The MAH will receive the adopted recommended submission date together with the request for supplementary information or followon request. The CVMP assessment of responses will take up to 30 or 60 days depending on the complexity and amount of data provided by the MAH. 4.2 Inform the rapporteur of the timeframe for the extension of the procedure. 4.3 Following adoption of the LoQ (or LoOI, if applicable) by the CVMP, send LoQ/LoOI to MAH, indicating the date 2 by which the requested data must be submitted 3. Update SIAMED. ToA and minutes of CVMP meeting to be updated, as applicable. Clock stop 4.4 Has the MAH submitted the additional/supplementary information on time? If yes, go to 4.6 If no, go to 4.5 4.5 Send reminder to MAH and agree new submission date, if necessary. Proceed to 4.4 4.6 Check that the rapporteur (and co-rapporteur, if applicable) received the responses. Update SIAMED and inform other services (DEM/APH/Compliance&Inspections), as applicable. Re-start the clock and send revised timetable to all CVMP members (CVE mailbox), if applicable, and to the MAH for information. Clock start 4.7 By day 30 after receipt of responses to LoQ/LoOI: Has the revised VAR been received in accordance with the timetable? If yes, go to 4.9 If no, go to 4.8 4.8 Send reminder to Rapporteur. Once revised VAR has been received, proceed to 4.9. 2 The date used is usually the recommended submission date for the following (or relevant) month. 3 The CVMP may also request oral explanations in addition to the written responses/data to be provided. The MAH would be informed of such a request in the letter sent with the LoQ/LoOI. SOP/V/4004 10-DEC-15 Page 12/17
4.9 Ensure that the rapporteur has sent the revised VAR on the responses to all CVMP members for comments (CVE mailbox), in case comments were only sent to Agency, forward them to CVE mailbox. 4.10 Send the revised VAR via Eudralink to the MAH for information. Update SIAMED. 4.11 By day 45 after receipt of responses to LoQ/LoOI: Ensure that comments of other CVMP members, EMA (if applicable), AWP and/or peer reviewer, if involved, were sent to all CVMP members (CVE mailbox). Proceed to 3.13 5.0 Adoption of CVMP opinion 4 5.1 By day 55: Generate draft CVMP Opinion/PI (as applicable) and draft CVMP VAR, based on the rapporteur s final VAR (which takes into account any CVMP comments). Review administrative information is accurate. Review and amend CVMP VAR regarding scientific information, as necessary. Check if other type IB or type IA variations were notified during the procedure, make sure they are taken into account in final PI (if applicable). 5.2 Include draft CVMP VAR and draft CVMP opinion/pi, for adoption, and rapporteur s AR, peer review reports and CVMP members comments in background information, as applicable, in CVMP mailing. In case of major changes (changes to the indication, addition of a non-food target species etc.) prepare SMOP. Check SMOP before inclusion in CVMP mailing for information. 5.3 Following adoption of an opinion (positive or negative), finalise the following set of documents: the opinion (to be signed by the Chair of CVMP) add as an annex the divergent positions of Committee members with their grounds, if applicable add other annex(es) (Annex A, I, II and/or III), enclose the scientific conclusions and/or the grounds for refusal, as appropriate the CVMP VAR. NB: Recommendations will be mentioned only in the assessment VROS/DEM/APH PM DEM/APH PM 4 Day 30, 60, 90 or after the end of the time extension SOP/V/4004 10-DEC-15 Page 13/17
report no need to follow-up. Conditions should be stated in the opinion and in the annex 2 of PI and tracked in SIAMED. 5.4 After the end of the CVMP plenary meeting: Update the CVMP ToA according to the outcome of the variation procedure. Submit the SMOP (if applicable) for publication with the CVMP press release. Review draft CVMP minutes. 5.5 Prepare post-opinion correspondence, and also check for a potential sweep and the need for a line listing Check post-opinion correspondence Send the CVMP opinion (with the amended Annexes (EN only), if applicable) and the CVMP VAR and PIPIT timetable (if applicable) to the MAH (via Eudralink) and to the EC (e-mail only). Send email to CVMP members (i.e. All-Veterinary CVE mailbox), including: Opinion (EN) and complete PI in EN CVMP VAR If applicable: Amended product literature incl. NO and IS (zipfile) Fill in QRD form following a linguistic review and return to the QRD inbox (E-SR-LRS). Finalise procedure in SIAMED set the status of the outcome as final. If variation is favourable, record the Scientific summary. NB: The summary text should read in case of a Commission Decision within 2 months The European Commission amended the decision granting the marketing authorisation to <shortened text from the precise scope> ; in all other cases, it should read The (European Medicines) Agency accepted the variation to <shortened text from the precise scope>. This will appear on the Steps taken after authorisation document published on the Agency website. Update the data in SIAMED which is affected by the favourable variation, e.g. manufactures, indications, list of presentations or presentations details, etc. Check that all translations have been provided electronically, including Icelandic, Norwegian, by Eudralink to Member States contact points (within 5 days after opinion). File relevant documents in core master file. 5.6 Does the MAH request re-examination of the opinion? If yes, go to 6.0 SOP/V/4004 10-DEC-15 Page 14/17
If no, go to 7.0 6.0 Re-examination 6.1 Was the re-examination request received in time 5? If yes, go to 6.3 If no, go to 6.2 6.2 Notify MAH that the deadline for notification of intention to request re-examination of the opinion has passed. Proceed to 7.0 6.3 Acknowledge receipt of the notification of intention to request reexamination. Include notification on the agenda of the next CVMP meeting. Prepare a cover page with a clear summary of the matter indicating the deadline for receipt of the grounds for re-examination and the likely time schedule for the evaluation. Update SIAMED. NB: CVMP will appoint a rapporteur, co-rapporteur and peer reviewers, if applicable, to assess the grounds for the request of the re-examination. The (co-) rapporteur and peer reviewer for the re-examination procedure should be different from the one(s) appointed for the initial assessment of the variation. 6.4 Inform MAH of the appointment of the rapporteur and corapporteur and confirm the deadline to provide grounds for reexamination. 6.5 Generate and prepare assessment report template for the reexamination of the opinion and send to rapporteur. 6.6 Upon receipt of the grounds for the re-examination, acknowledge receipt. Prepare a draft timetable for the re-examination procedure and agree it with the rapporteur and co-rapporteur. Ensure they have received the documentation. Include the topic on the agenda for the next CVMP meeting, and include the grounds for the re-examination as well as the timetable. Update SIAMED. 6.7 Was the rapporteurs assessment received in accordance with the timetable? If yes, go to 6.9 5 Receipt of written notice of the intention to request re-examination of the CVMP opinion within 15 days of receipt of the opinion by the MAH: Days are counted as calendar days. The period starts on the day following receipt of the opinion. Where the last day in a specific period falls on a Saturday, Sunday or Public Holiday the following working day will be considered as the final day. The day of receipt of the opinion is the day when the MAH received email notification/fax. SOP/V/4004 10-DEC-15 Page 15/17
If no, go to 6.8 6.8 Remind rapporteur to send written assessment of grounds for appeal. 6.9 Update SIAMED. Ensure that the rapporteur has sent the assessment of the grounds for re-examination to all CVMP members for comments (CVE mailbox), in case comments were only sent to Agency, forward them to CVE mailbox. 6.10 Liaise with rapporteur and CVMP to decide on need for further explanations from the MAH to be provided orally. Are oral explanations required or have been requested by the MAH? If yes, go to 4.3 If no, go to 5.0 7.0 Post opinion 7.1 Once the deadline for requesting re-examination has passed (day 15 after opinion): Is there a need to draft an EPAR VAR ( significant variations)? If yes, go to 7.2 If no, go to 7.4 7.2 Draft CVMP VAR and send to applicant for deletion of confidential information and copy rapporteur (2 weeks deadline). Review comments 6 received Save document as the EPAR VAR (CVMP VAR with confidential information deleted). HSer 7.3 Process EPAR update in accordance with SOP/V/4038. / 7.4 Within 30 days of having received commission decision: Save commission decision in relevant folder in Dream and update name of the folder with date of commission decision. Update Siamed with changes, if appropriate. 7.5 In case of a Corrigendum: Liaise with Commission to agree the terms of the Corrigendum After receipt of Commission Corrigendum: Ensure electronic copies of amended product information has been received Save latest version of product literature as: o Post-Authorisation/Commission Decision/Current Annexes 6 According to Principles to be applied for the deletion of commercially confidential information for the disclosure of EMA documents (EMEA/45422/2006) SOP/V/4004 10-DEC-15 Page 16/17
<DATE> o o Send Corrigendum to applicant (electronic version) if applicable If appropriate, check mock-ups 7.6 File relevant documents in core master file. Proceed to 8.0 8.0 End of process 10. Records The originals of received correspondence are archived in the product master file. Electronic copies are saved in the appropriately labelled folder in DREAM. Electronic submissions of application and responses to list of questions or list of outstanding issues are saved in EURS. Amended Annexes (if applicable) are saved in DREAM in the procedure folder, in its subfolder Translations. Electronic versions of acknowledgments of receipt (where applicable), scanned copies of all signed correspondence, relevant emails to the MAH and Rapporteur (if necessary) are saved in DREAM in the procedure folder. Paper copies of all other correspondence related to the procedure should be stored in temporary filing area by their date of submission/issue and discarded after 6 months have elapsed from the date of issue/submission. The crucial procedure documents are to be saved in DREAM product folder and declared as records for long (30-year) preservation by adding them to the electronic cmf, in accordance with SOP/PDM/1004 and the cmf checklist applicable to the procedure. SOP/V/4004 10-DEC-15 Page 17/17