ARTICLE OF THE YEAR: The linguistic review process in the centralized procedure in the EU

In the EU and European Economic Area (EEA), certain products receive marketing authorization through the centralized procedure (CP). Following this, a number of documents, such as the product information (PI), require translation into all 24 EU and EEA official languages. The translations provided by the marketing authorisation holder (MAH) are approved by the corresponding EU member states. This review and approval process of the 24 languages is known as the linguistic review procedure and involves a number of parties and multiple steps, and is also applicable for postapproval changes. The procedure is discussed within this article.
 

Introduction

Certain products in the EU and European Economic Area (EEA), such as biological compounds or new medicines with new active substances to treat certain diseases, receive marketing authorization through the CP.¹ The European Medicines Agency (EMA), and in particular, the Committee for Medicinal Products for Human Use (CHMP), assesses the entire application and makes a recommendation to the European Commission (EC) who make the final and legally binding decision on whether the medicine is approved for marketing within any country in the EU.² The application process for centrally authorized products (CAPs) is conducted in English, although there are a select number of documents, which require translation into all 24 EU/EEA languages, as per the official languages per country, such as the product information (PI).³
 
The PI are a group of documents which are approved at granting of a marketing authorization and contains official approved information for healthcare professionals and patients to inform on a medicine.⁴ The document comprises of the summary of product characteristics, labelling, and package leaflet. A template and guidance for the preparation of the PI is provided by the EMA Working Group on Quality Review of Documents (QRD) and it must be used for any marketing authorization application (MAA) granted through the CP. During the MAA period, the English PI is reviewed and approved. This PI must be translated into all 24 EU and EEA languages, and each one must be approved by the corresponding EU member states. This review and approval process of the other 24 languages is known as the linguistic review procedure.
 
The linguistic review of the PI is an essential process to ensure high-quality and accurate translations of the approved English PI for CAPs in the EU. This process occurs after positive opinion from the CHMP. As detailed in Articles 9, 10, 34, and 35 of Regulation (EC) No. 726/2004⁵ and Articles 20 and 23 of Regulation (EC) No. 1234/2008,⁶ linguistic review of the product information, post-CHMP opinion, is essential before the final commission decision. The review is conducted in all EU languages, as well as Norwegian and Icelandic, within strict timelines and is applicable to all marketing authorizations, extensions, and other postauthorization procedures that affect the PI. The EMA has published a guideline on the product information linguistic review process⁷ and provides details on its practical implementation.
 

Linguistic review process

The review of the 24 language PIs is performed by EU-EEA member states over a 2-week period each month. The general timelines, including the key steps of the process, are presented in Figure 1. A discussion on the specific processes for procedures – including MAAs, variations, and referrals for CAPs that affect the PI – are discussed within.
 

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Initial marketing authorizations and extensions
During the assessment of a marketing authorization (pre-CHMP opinion), the English PI document containing the summary of product characteristics (SmPC), labelling, and package leaflet text, is reviewed by the agency. The reviewers include the Technical Labeling Review group, the QRD group, the Patients’ and Consumers’ Working Party, and EMA medical writers. All comments should be addressed by the applicant when the revised English PI is submitted at Day 181, and the agency will check that the technical labeling review comments have been implemented before CHMP opinion. The key time points from Day 1 to Day 277 are displayed in Figure 2.
 

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Key timelines and documentation required at each time point during the linguistic review period for initial marketing authorization applications and extensions are presented in Figure 3. After the adoption of a positive opinion at Day 210, the marketing authorization holder (MAH) sends the final English PI to the agency at Day 215. Translations of the English PI, Annex IV, Annex 127a (if applicable), and Annex A into all 24 EU languages, need to be provided to the agency as Word documents on Day 215. The PI translations are typically started before the final English PI is available, usually around Days 150-180. In addition, the submitted package should also include the Day 215 checklist and QRD form 1. QRD form 1 comprises of two parts: Part 1, which contains administrative information; and Part 2, which is populated by the member state reviewer and provides feedback on the quality of the translations. Part 2 of QRD form 2 can be used internally by MAHs, as a key performance indicator.
 
The EMA initiates the linguistic review period and distributes the translated documents to the individual member states for review. The member states have two weeks to review the documents and will return the tracked changed documents with their comments, directly to the MAH, by Day 229, together with Part B of QRD form 1.
 
Following receipt of the reviewed files, the MAH proceeds to finalize the documents. Should the MAH not agree with some edits in the PI, it must communicate with the member state reviewer until the two parties reach agreement. If the MAH does not address all the reviewers’ comments, the MAH must state this in QRD form 2 and provide a valid justification. A tracker is a valuable tool for MAHs during the linguistic review period, especially when liaising with individual member states. It is also worth noting that occasionally, edits by the member state reviewer will be made in one SmPC, labelling section or patient information leaflet (PIL) only, so should an edit be applicable to multiple sections, they must be transferred by the applicant to the different strengths/sections.
 
By Day 235, all 24 language files should be reviewed, finalized, and submitted to the EMA procedure manager (PM). The submission, made via Eudralink,⁸ should contain:
 

• 25 clean Word and PDF PIs (24 languages plus English),
• Annotated Word Annex A documents (if necessary),
• 25 clean PDF Annex As,
• The populated international non-proprietary name table (MAA only),
• QRD form 2, and
• Annex 127a, if required.

 
To note, all PI and Annex A documents should be named as per the EMA naming convention and bookmarked and should contain the correct document properties⁹ and be formatted as per the QRD requirements.¹⁰
 
The agency will check if all member states’ comments have been implemented and will then send the final translation to the EU Commission. The commission will then start the 22-day standing committee consultation.
  

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Type IA and IB variations and Article 61(3) notifications
Variations are postapproval changes to the terms of a marketing authorization, including the documentation, such as the PI. The Commission Regulation (EC) No. 1234/2008 (Variations Regulation) and the commission 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 and on the documentation to be submitted pursuant to those procedures (Classification Variations Guidelines), provide a list of changes with an assigned variation type.¹¹
 

• Type IA variations are minor changes that have minimal or no impact on the quality, safety, or efficacy of the medicinal product and do not require prior approval before implementation. This is known as the do and tell procedure.
• Type IB variations are also minor variations, but they must be notified to the EMA by the MAH before implementation, although a formal approval is not required – the tell, wait, and do procedure).
• Article 61(3) can be found in Directive 2001/83/EC,¹² where a 61(3) notification is defined as change to an aspect of the labelling and/or package leaflet, not connected with the summary of product characteristics.

 
Not all type IA and type IB variations affect the PI, but for those that do, and for all Article 61(3) notifications, annotated Word and clean PDF PIs are included in the submission of the variation package. For type IA variations (and some Article 61(3) notifications), there is no linguistic review and the submission package must include the nonlinguistic review checklist.¹³ For type IB variations and some Article 61(3) notifications, all annotated and clean annexes must be provided at submission, but often linguistic review is required. The linguistic review period follows a similar timetable to that for the previously described MAA and extensions. However, linguistic review does not occur after a positive CHMP opinion. Day +5 (D+5) will start after agency validation of the submission on Day 7. For type IB variations, linguistic review takes place in parallel with the scientific assessment (Figure 4).
 

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At D+5, the annotated Word documents are submitted directly the member states via Eudralink (not to the EMA PM as described for MAAs and extensions above), ensuring the most recent version of the member states contact details are used.¹⁴ Linguistic review of the annexes is performed by the member states over a 2-week period and by D+19, the MAH should have received all 24 reviewed PIs, and proceeds to finalize them for submission at D+25. The submission should contain 25 annotated Word and clean PDF PIs (and Annex A if necessary) and QRD form 2. Linguistic review is conducted in parallel with the scientific assessment, so changes could be required in the English PI, after linguistic review has completed. In this unlikely event, the changes must be made in the 24 language PIs and often, linguistic review will need to be initiated again the following month.
 
For Article 61(3) notifications, all annotated Word and clean PDF documents are submitted at Day 0 and the MAH is informed if linguistic review will be required. This depends on the changes required on the labelling and/or package leaflet. The linguistic review period will proceed with the key time points: D+5, D+19, and D+25 (Figure 5).
 

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Type II variations
Under Commission Regulation (EC) No 1234/2008,¹⁵ a Type II variation is defined as a major (postapproval) variation that is not an extension of the marketing authorization but may have a significant impact on the quality, safety, or efficacy of a medicinal product. As with other variations, the variations regulation sets out a list of changes that are deemed Type II variations.
 
For these variations, the overall process follows that presented in Figure 6. The English PI is submitted for review and translations are provided at D+5, with reviewed files returned by member states by D+19 and final annotated and clean files submitted to the agency by D+25. For procedures that start on a weekly basis, the linguistic review period will follow the monthly review cycle, starting 5 days after the next CHMP plenary meeting. The advantage of this in regard to the linguistic review procedure is that it provides additional time for the MAH to complete the translations between CHMP opinion and D+5. Final commission decision for Type II variations is obtained on Day 75.
 

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Annual re-assessment and renewals
The linguistic review period for annual re-assessments and renewals follows the timetable shown in Figure 1. If the changes affect only Annex II, the agency can consider shortening the linguistic review timetable. Final commission decision for renewals is obtained on Day 67.
 
Grouped variations
For the submission of grouped variations, the linguistic review process will proceed according to the highest procedure in the group. For example, for a grouped extension and Type II variation, the linguistic review process and timetable will follow that of an extension. For a grouped Type II and Type IB variation, the process and timetable will follow that for a Type II variation.
 
Worksharing procedures
An MAH can submit the same type IB or type II variation (or the same group of variations affecting more than one marketing authorization from the same MAH) in one application. This is known as a worksharing procedure.
 
For worksharing procedures (type II and type IB) including at least one CAP, the general procedure and documents for submission have been described in the preceding Type II variations and Type IB variations (with linguistic review) sections. At initial submission, the English PI for all products is submitted. However, only one set of annexes for one CAP, is submitted at D+5 for linguistic review. Following review of the PI by the member states, the MAH must implement the same edits into the other product PIs and by D+25, all annotated and clean documents for all affected products are submitted in the final D+25 submission package.
 
Safety signals
On a monthly basis, following the Pharmacovigilance Risk assessment Committee (PRAC) meeting, a listing of all safety signals discussed at the meeting are published. Safety signals are usually Type IB variations. For PI updates resulting from safety signals, standard wording, which ensures consistency across products, is provided by the agency (PRAC recommendations on safety signals) in all 25 languages. The wording can be found on the EMA website.¹⁶ The provided wording is implemented into all 25 languages and the annotated Word and clean PDF files are submitted to the agency.
 
PSUR and PSUSA procedures affecting the PI
A periodic safety update report (PSUR) is a global pharmacovigilance (PV), postmarketing document containing all the necessary safety information, worldwide experience, and evaluation of the benefit-risk balance of a medicinal product at specific time points after authorization. A periodic safety update report single assessment (PSUSA) is a single assessment conducted by the EMA, of related PSURs pertaining to different marketing authorizations with the same active substance or combination of active substances for which the frequency and PSUR submission dates are harmonized in the list of EU reference dates (EURD).¹⁷ The aim of the assessment is to harmonize and strengthen the benefit-risk review of medicines across the EU and EEA.¹⁸ The outcome of the PSUSA can require an update to the wording in the PI. The updates are implemented into the English PI and the linguistic review period is implemented to update the EU and EEA languages.
 
The linguistic review milestones follow the same timelines as those in Figure 7. Following a positive CHMP opinion, the English PI will contain an additional annex – Annex IV (scientific conclusions) – inserted by the CHMP. Upon receiving this file, the MAH must have Annex IV translated in all 24 language files, ready for submission at D+5. D+19 and D+25 proceed as normal. The final D+25 files will contain the additional Annex IV section, which would be removed at the next procedure affecting the PI. Final commission decision for PSUSA procedures is obtained on Day 67.
 

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Article 20 and Article 31 referrals and Article 29 (pediatrics) procedures
A referral procedure is used to resolve issues such as safety or quality concerns. Article 20 (for CAPs only) and Article 31 (for CAPs and nationally authorized products) procedures are both PV referrals that are for medicines following quality, safety or efficacy issues of a medicine or class of medicines. The Article 20 PV referral follows the provision of Article 20 outlined in Regulation (EC) 726/2004¹⁹ and Article 31 as outlined in Article 31 of the Directive 2001/83/EC.
 
The Article 29 pediatrics procedure of Regulation (EC) No 1901/2006²⁰ is an optional procedure tiggered by an MAH applying for an extension of indication, new pharmaceutical form, or new route of administration for use in the pediatric population for a product authorized according to Directive 2001/83/EC. For these procedures, and when required, the English PI is updated, submitted, and reviewed during the scientific referral assessment. Following, approval of the English PI, the linguistic review period is initiated and generally follows the same timelines as per Figure 8, with some minor differences. D+25 is brought forward to D+22. At D+22 following CHMP Opinion, all final Word and PDF files together with QRD form 2 is submitted to the EMA PM, with transmission to the Commission occurring at D+27.
 

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Generics, hybrids, and biosimilars
The overall review and milestones for generics, hybrids and biosimilars, follows that for MAAs. However, for generics, only a technical labelling review, performed by the agency, is required by Day 180. For hybrids and biosimilars, the technical labelling review is performed by the agency and member states. The PI for generics, hybrids, and biosimilars should follow that of the reference product, apart from specific sections (e.g., quality), although format changes to align with the QRD requirements are permitted. For hybrid or generic products, an additional English PI document highlighting the differences from the reference PI should be submitted in the package at Day 215. If linguistic review for the generic, hybrid, or biosimilar occurs at the same time as the reference product, the agency will send the translations to the MAH of the generic, hybrid, or biosimilar product upon receipt of the final reference product documents and request updated translations within 2 days.
 
Conclusion
An overview of the key documents for the varying linguistic review procedures are presented in the table below. In general, a similar timetable and set of documents are required for each of the different procedures, with some minor differences.
 

 
The linguistic review process for CAPs within the EU and EEA is a refined and detailed procedure that is not only a vital step following a positive CHMP opinion, but it is an important process in maintaining accurate, consistent, and high-quality PI documents for healthcare providers and patients in the EU. The diversity of languages makes this a challenging part of the submission process.
 
Abbreviations
CAP, centrally authorized product; CHMP, Committee for Medicinal Products for Human Use; CP, centralized procedure; EEA, European Economic Area; EMA, European Medicines Agency; EN, English; EU, European Union; LE, line extension, LR, linguistic review; MAH, marketing authorization holder; MS, member state; PI, product information; PM, procedure manager, PRAC, Pharmacovigilance Risk Assessment Committee; PSUR, Periodic Safety Update Report; PSUSA, Periodic Safety Update Single Assessment; PV, pharmacovigilance; QRD, quality review document; SmPC, summary of product characteristics.
 
About the author
Emma Yang, PhD, is a senior regulatory affairs consultant at Parexel International. She can be contacted at emma.yang@parexel.com
 
Citation Yang E. The linguistic review process in the centralized procedure in the EU. Regulatory Focus. Published online 29 October 2021. [Link]

References
All references with URLs were accessed on 27 October 2021.
 

1. European Medicines Agency. Authorisation of medicines. Last updated 2 October 2020. https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines#scope-of-the-centralised-procedure-section
2. European Medicines Agency. From laboratory to patient – The journey of a medicine assessed by the EMA. Published 2019. https://www.ema.europa.eu/en/documents/other/laboratory-patient-journey-centrally-authorised-medicine_en.pdf
3. European Medicines Agency. List of official languages per country. Published 1 January 2021. https://www.ema.europa.eu/en/documents/other/list-official-languages-country_en.pdf
4. European Medicines Agency. Product information [definition]. Not dated. https://www.ema.europa.eu/en/glossary/product-information
5. European Parliament and Council. Regulation (EC) No 726/2004 of 31 March 2004.  https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32004R0726&from=EN
6. 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. https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-1/reg_2008_1234/reg_2008_1234_en.pdf
7. European Medicines Agency. The linguistic review process of product information in the centralised procedure – human (EMEA/5542/02/Rev 5.1). https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/linguistic-review-process-product-information-centralised-procedure-human_en.pdf
8. Eudralink portal. Eudralink (europa.eu)
9. Generating PDFs user guide. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004716.pdf
10. QRD convention to be followed for the EMA-QRD templates. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500005091.pdf
11. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure. Microsoft Word - Post Authorisation Guidance-Integrated Version - clean - Apr 2021 (europa.eu)
12. Directive 2001/83/EC of the European Parliament and of the Council. 28263005en 67..100 (europa.eu)
13. Non-linguistic review checklist. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2015/12/WC500198938.pdf
14. Contact points for member states. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004437.pdf
15. Commission Regulation (EC) No. 1234/2008. LexUriServ.do (europa.eu)
16. PRAC recommendations on safety signals. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000375.jsp&mid=WC0b01ac0580727d1c
17. Definition of EURD list. EURD list | European Medicines Agency (europa.eu)
18. Periodic safety update reports (PSURs) from the EMA. Periodic safety update reports (PSURs) | European Medicines Agency (europa.eu)
19. Regulation (EC) No. 726/2004 of the European Parliament and of the Council. untitled (europa.eu)
20. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council. l_37820061227en00010019.pdf (europa.eu)