Classification of changes: questions and answers
This page is intended to provide advice to Marketing Authorisation Holders of centrally authorised medicinal products about classification of changes to the Marketing Authorisation post-authorisation and certain variation classification categories. Revised topics are marked 'New' or 'Rev.' upon publication.
A PDF version of the entire post-authorisation guidance is available:
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure (with track changes)
It should be read in conjunction with the European Commission 'Variations Guidelines' 2013/C 223/01 and the CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008.
MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.
1.1. How should I submit changes to date of the audit to verify GMP compliance of the manufacturer of the active substance? (Classification category A.8)
According to the 'Variations Guidelines' 2013/C 223/01, this variation does not apply when the information has been otherwise transmitted to the authorities (e.g. through the so-called “QP declaration”). Otherwise transmitted means that the information has been provided to the competent authorities within any formal regulatory procedure e.g. renewals, variations. In these cases, no separate variation application for the change in the audit date has to be submitted. However, the change has to be mentioned in the scope of the application form as well as under "present/proposed" but not in the section “variations included in this application.”
Manufacturer of finished product (as referred under documentation requirement 1 of classification category A.8) means any registered EEA manufacturers of medicinal products (finished product and batch release) which hold a valid manufacturing authorisation. This is the same as manufacturing sites which are required to provide a qualified person declaration, where a single declaration may be acceptable under certain circumstances – see note below under section on Quality Changes – Classification category B.II.b.1.
2.1. Introduction of a new manufacturing site for the finished product. What changes can I submit under a single type II scope? (Classification category B.II.b.1)
The following complex related changes could be considered for submission under a single type II scope B.II.b.1 - Addition of a new finished product (FP) manufacturing site: changes to the manufacturing process, batch size and in-process controls to adapt to the new manufacturing site settings.
Complex related changes submitted under a single type II should always be clearly identified in the application form as following: a clear description of all the related changes should be provided in the precise scope. All the related changes should be listed in the present/proposed table.
Changes affecting the FP not directly related to the introduction of the new manufacturing site such as changes in excipients, specification parameters /limits for the FP, container closure system including suppliers should be submitted as additional variation scopes.
Any pre-submission queries of any intended submission of complex related changes under one single type II scope should be addressed to the appointed Procedure Manager.
2.2. Introduction of a new manufacturing site for an active substance. What changes are covered by a single type II scope? (Classification categoryB.I.a.1) New June 2017
The introduction of a new manufacturing site for an active substance supported by an ASMF should be submitted under a single Type II scope B.I.a.1.b. The introduction of a new manufacturer of the active substance not supported by an ASMF that requires significant updates to 3.2.S should be submitted under a single Type II scope B.I.a.1.g).
It should be noted that in cases where the introduction of the new active substance manufacturer has an impact at the level of the finished product manufacturer (e.g. changes to the active substance specifications or related analytical methods) separate variations have to be submitted under the corresponding B.I.b. categories and may be grouped together, if related to the introduction of the new active substance manufacturer.
Any pre-submission queries related to upcoming submissions pertaining to such changes should be addressed to the appointed Procedure Manager.
2.3. How should a change to Module 3.2.S or the update of an ASMF, which is part of Module 3 (human) of a marketing authorisation be submitted? (B.I.z) New June 2017
An update or change of a stand-alone ASMF is not foreseen and can only be addressed in connection with a marketing authorisation. The type of the variation(s) is dependent on the type of the single changes introduced in the updated version. The update – including changes to the open and /or restricted part - can be submitted as a grouped application, if condition 5 of Annex III of the Variation Regulation (EC) No 1234/2008 applies.
However, in case of substantial changes in the updated version of Module 3.2.S or the ASMF it is recommended to submit a single type II variation under category B.I.z. However, it is a prerequisite for the validation of these single variations that the “present/proposed” section of the application form is filled in correctly and completely.
In all cases, updates of the ASMF must be submitted by the ASMF holder (open and closed part to EMA, open part to marketing authorisation holder) whilst the variation as such has to be submitted by the marketing authorisation holder. We encourage a close dialogue between MAH and ASMF holder to establish the correct classification of all the changes introduced within a new version of an ASMF to avoid validation issues.
Any pre-submission queries related to upcoming submissions pertaining to such changes should be addressed to the appointed Procedure Manager.
2.4. How should I submit an updated Certificate of Suitability (CEP)? (Classification category B.III.1)
In line with the Marketing Authorisation Holder's (MAH) obligation to keep the dossier up to date, a new or updated Certificate of Suitability (CEP) for an active substance (AS), excipient or starting material/reagent/intermediate used in the manufacturing process of the AS should be submitted as a variation. It is however understood that only the versions of the CEP (i.e. updated certificates) which were used in the manufacturing process of a batch of finished product (FP)/ AS need to be included in the dossier.
CEP updates should be submitted under the appropriate variation classification scope within subsection B.III.1. Each CEP update should be submitted as a variation scope, i.e. an update covering more than one CEP version should be submitted as a grouped variation.
When applying for an update of an approved CEP, the MAH should refer to the previously agreed version of the CEP within the 'Present/Proposed' section of the application form.
If with the submission one or more revisions of the CEP are omitted, the MAH should confirm in the variation application form (section 'Precise scope and background for change') that substance/material from the omitted CEP version(s) was not used in the manufacture of the FP and/or AS during the validity of this certificate(s). Additionally it should be confirmed that any changes introduced by the omitted CEP update(s), do not affect the quality of the AS and/or FP. In case such confirmation is missing, a negative Type IA notification may be issued.
The MAH should also clearly indicate in the 'Present/Proposed' section all changes introduced in the CEP between the latest approved version and the new revision, including all revisions that were not notified. Any changes e.g. to manufacturing sites, additional residual solvents introduced in the CEP by subsequent updates should be declared.
Submission of an updated CEP version for an already approved manufacturer: R0-CEP-xxxx-xx-rev.02 when the current certificate in the dossier is: R0-CEP-xxxx-xx-rev.00.
If during the validity of R0-CEP-xxxx-xx-rev.01, material of the CEP was used in the manufacture of the FP and/or the AS, then the MAH should submit a grouping of two IA variations to include both certificates (rev. 01 and rev. 02) in the Module 3. The foreseen conditions for each of the respective variations should be met.
If during the validity of R0-CEP-xxxx-xx-rev.01, material of the CEP was not used in the manufacture of the FP and/or AS, the MAH should only submit a single Type IA variation to include the updated certificate R0-CEP-xxxx-xx-rev.02 in Module 3. The foreseen conditions for the variation should be met.
The MAH should also confirm in the variation application form that material/substance from R0-CEP-xxxx-xx-rev.01 was not used in the manufacture of the FP and/or AS during the validity of this certificate and that changes introduced by the revision R0-CEP-xxxx-xx-rev.01 do not affect the quality of the AS and/or the FP. MAH should also clearly list within the 'Present/Proposed' section of the application form all changes introduced to the CEP with revisions 01 and 02.
2.5. What is considered to be a non-significant in-process control or specification parameter? (Classification category B.I.a.4.c, B.I.b.1.d, B.I.c.2.c, B.II.b.5.c, B.II.c.1.c, B.II.d.1.d, B.II.e.2.c and B.IV.2.f)
Variation scopes B.I.a.4.c, B.I.b.1.d, B.I.c.2.c, B.II.b.5.c, B.II.c.1.c, B.II.d.1.d, B.II.e.2.c and B.IV.2.f of the 'Variations Guidelines' 2013/C 223/01, deal with the deletion of a non-significant in-process control (IPC) test or specification parameter. Provided all relevant conditions and documentation requirements are met, all these variations fall under the Type IA category (do-and-tell).
For the categories listed above and other variations related to specifications of active ingredients, excipients, finished product, packaging material or measuring or administration device, the deletion of an obsolete parameter is given as an example. For finished products, this is further exemplified by mentioning of odour and taste. Although it is not possible to give similar examples for all of the categories mentioned above, these examples serve as an indication of the types of changes considered to fall under this variation category, regardless if this is related to in-process controls or specifications. This is therefore intended to be used for truly obsolete tests that are no longer part of normal specifications for newer products, but have remained for historical reasons in older products.
This variation category is not intended to include changes in relation to revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical) that are tested at different stages during the production, or cases where process/ product characterisation performed after authorisation has shown that the attribute/ parameter is non-critical. Such changes require regulatory assessment and are to be handled as Type IB or II variations as appropriate.
2.6. When applying for a new pack size, what is considered to be within /outside range? (Classification category B.II.e.5) New Jun 2017
The introduction of a new pack size (i.e. in addition to currently approved pack sizes) should be submitted as a variation under scope B.II.e.5.a).
A range is defined from the smallest to the largest approved pack size (i.e. not from '0') for the same pharmaceutical form and strength. The pack size equals to the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained in the outer packaging. Pack sizes not included within this range are considered to be outside of the range.
For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a IAINvariation B.II.e.5.a.1.
For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a IB variation B.II.e.5.a.2.
In support of a timely introduction of new pack sizes to the market, EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as IB variation B.II.e.5.a.2. This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as IAINvariation B.II.e.5.a.1.
The “Medicinal Product A” has currently two approved pack sizes of 30 and 60 tablets for the pharmaceutical form“film coated tablets” and the strength “20mg” and the MAH intends to apply for two new pack size(s) of 90 and 120 tablets at the same time.
The introduction of a new pack size of 120 tablets for the “20mg” strength is considered outside the range of packs and should be classified as variation B.II.e.5.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets as a grouped (or a latter) submisison can be classified as a variation B.II.e.5.a.1 (IAIN).
The “Medicinal Product B” has currently two approved pack sizes of 2 and 10 pre-filled syringes for the pharmaceutical form “solution for injection” for both strengths of “20mg” and “40mg”.The MAH is applying for four new pack sizes:5 prefilled syringes for the “20 mg” strength; 30 pre-filled syringes for the “20 mg” strength; 5 prefilled syringes for the “40 mg” strength; 30 pre-filled syringes for the “40 mg” strength.
For the “20mg” strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.1 (IA) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).
For the “40mg” strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.1 (IA) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).
The MAH should therefore apply for a grouped variation application under the scopes referred above.
It should be highlighted, that for variations introducing additional presentations or pack sizes for centrally approved products, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation and pack size should therefore be declared as a separate variation on the variation application form under the section 'variations included in this application'.
For additional guidance on changes to existing presentation that can trigger new EU number(s) please see the EMA post-authorisation guidance for Type IA, Type IB and Type II variations.
2.7. How should I submit a new working cell bank (WCB)? (Classification category B.I.a.2 a) New June 2017
If a new WCB is introduced using the limits/conditions as detailed in an approved qualification protocol, the new WCB is covered by the existing quality assurance system and there is no need to submit a variation.
If the documentation of the WCB in the dossier does not include an approved qualification protocol for introducing new WCBs, the MAH should file a variation B.I.a.2 a type IB (as condition 5 is not met).
To introduce a qualification protocol for preparation of a new WCB, the MAH should file a variation type II B.I.a.2.c. The addition of the new WCB can be covered as part of this single variation type II.
Changes to an approved standard procedure (protocol) should be filed using a variation type IB B.I.a.2.a, or a variation type II B.I.a.2.c, as relevant depending on the complexity of the change. The addition of a new WCB can be covered as part of this single variation.
2.8. How should I submit a new reference standard for a biological medicinal product? New June 2017
If a new reference standard is introduced using the limits/conditions as detailed in an approved qualification protocol, the new reference standard is covered by the existing quality assurance system and there is no need to file a variation.
If no qualification protocol has been approved and the old material is still available and the MAH is able to provide comparability test results using both reference standards, the MAH should file a type IB variation either under B.I.b.2.e for Active Substance or under B.II.d.2.d for Finished Product.
If no qualification protocol has been approved and the old material is not available anymore and therefore no direct comparison new/old material is possible the MAH should file a type II variation either under B.I.b.2.d for Active Substance or under B.II.d.2.c for Finished Product.
To introduce a qualification protocol for the preparation of a new reference standard, the MAH should file a variation type II either under B.I.b.2.d for Active Substance or under B.II.d.2.c for Finished Product. Upon approval of the variation, the introduction of a new reference standard according to the protocol will be covered by the existing quality assurance system.
2.9. What changes in manufacturing sites, buildings and rooms are covered by the company Quality Assurance System (GMP)? Rev. May 2018
Provided that module 3 is not impacted, with the exception of section 3.2.A.1 (for biological medicinal products), the changes listed below (not an exhaustive list) are covered under the company's quality management system and do not require a variation to the Marketing Authorisation:
- Transfer of a manufacturing activity from one building to another in the same authorised site
- Transfer of a manufacturing activity from one room to another in the same authorised building
- Transfer of QC activity from one building to another in the same authorised site
- New filing line identical to an already approved onein an authorised room, building, manufacturing site
- New isolator in an authorised building
- New media or buffer preparation room in an authorised building
- Changes in the layout of an authorised manufacturing site
If as a result of any of the changes listed above, any amendments are introduced to module 3 (with the exception of section 3.2.A.1 for biological medicinal products), such as changes to the manufacturing site address detail, changes to the manufacturing process, changes to the batch size, etc., the MAH should file the appropriate variation(s).
2.10. Changes in equipment used in the manufacturing process. What changes are covered by the company Quality Assurance System (GMP)? Rev. May 2018
Provided that the new equipment is equivalent to the one currently used, and operates in the approved range of process parameters, the change is covered by company's quality assurance system.
If the introduction of new equipment has any impact on the processes and details registered in module 3 (with the exception of section 3.2.A.1 for biological medicinal products), the MAH should submit the appropriate variation(s).
2.11. How should I update section 3.2.A.1 for Biotech medicinal products? New June 2017
Notice to applicants for Medicinal products for human use (Eudralex – Volume 2B) establishes that information on facilities and equipment should be included in Appendix 3.2.A.1 for biotech medicinal products.
Any update of this section can be included as part of any upcoming variation affecting Module 3. In case the MAH wants to update this section and does not foresee any upcoming variation affecting Module 3 in the short/medium term, the MAH may consider submitting a Type IB variation (B.II.z).
2.12 What do I need to consider if there are any changes to my medical device post-authorisation? New August 2017
Commission Regulation (EC) No 1234/2008 ('the 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” ('the Variations Guidelines') defines the conditionsand requirements which must be met for any change (addition or replacement or deletion) to a measuring or administration device (classification B.IV.1). Depending on the change, the variation can be classified as either type IA(IN), IB or II. Given the relatively short timelines for variation procedures, for medical devices that do not form a single integral product at time of placing on the market and which are co-packaged with the medicinal product, the CE mark must be submitted as part of the documentation at time of submission of the variation to avoid any delays. The published timelines for the submission and evaluation of the respective variation will be followed.
3.1. How should I submit a study protocol?
For imposed, non-interventional safety studies, the initial protocol submission should follow the provisions under Article 107n of Directive 2001/83/EC. Major amendments of such study protocol should be submitted under the provision of Article 107o of Directive 2001/83/EC (please also refer to guidance on PASS).
For other studies (i.e. non-imposed studies and/or interventional studies), if the initial assessment or the amendment of a study protocol does not result in a consequential change of the condition as reflected in Annex II and/ or the description of the study in the RMP it can be provided as a post-authorisation measure (PAM) (please also refer to guidance on post-authorisation measures).
Once agreed, the MAH can take the opportunity of a regulatory procedure affecting the RMP to include the final updated protocol in the appropriate RMP annex(es).
If the study description in the Annex II condition and/ or in the RMP is affected, the study protocol/ or the protocol amendment, together with the proposed updated Annex II and/or RMP should be provided as part of a type II variation application under category C.I.11.b.
3.2. How should non-clinical and/or clinical study reports be provided?
In line with the 'Variations Guidelines' 2013/C 223/01 all 'final' non-clinical or clinical study reports concerning a marketing authorisation granted under the centralised procedure will have to be submitted to the Agency as part of a type II variation application, unless otherwise specifically covered in the annex to the classification guideline on variations or listed below:
- Results of imposed non-interventional safety studies covered by the Art. 107q of the Directive 2001/83/EC;
- Submissions of final study results in support of extension of marketing authorisation applications, annual renewals or annual re-assessments;
- Submission of study results related to paediatric population in line with Article 46 of Regulation 1901/2006. Submissions pursuant to Article 46 should continue to follow the procedure for post-authorisation measures, unless the MAH concludes that changes to the product information (PI) are warranted based on the data submitted. In such cases, the relevant variation should be submitted;
- Studies in the context of an environmental risk assessment (ERA). These are expected to be assessed during the initial marketing authorisation or relevant post-marketing procedures (e.g. extension of indication, extension applications). In the exceptional case that ERA study results are provided stand-alone, they should be submitted as a type IB C.1.z variation;
- Results including reports from bioequivalence studies to support quality changes to the marketing authorisation should be submitted under the applicable variation category for quality changes.
As a general rule, the 'final' study report is considered the one including the primary analysis of the study. In case the final study report has previously been submitted, further updates of data from the study without formal statistical significance after the primary analysis do not trigger additional variations, unless they lead to changes to the product information and/or to the Risk Management Plan (RMP). On the other hand, a formal extension study, generally with a different study design and objectives as compared to the initial study, is considered a separate study and it generally carries a separate study number. The submission of the final report for such an extension study triggers a variation.
When a change to the product information is proposed as a consequence of the final study report, the type II variation should be submitted under variation classification categories C.I.6 (extension of indication), C.I.4 (other changes involving the SmPC, Annex II, labelling and/or Package Leaflet) or C.I.11 (changes limited to the Annex II conditions). When no changes to the product information are proposed, the variation should be submitted under category C.I.13.
When a final non-clinical or clinical study report is provided as part of a variation submitted under category C.I.13, it should be noted that one separate type II variation per study report is required. This requirement applies also in situations where the CHMP has requested several non-clinical or clinical studies to be undertaken as part of a specific post-authorisation measure (PAM) in order to address a specific issue; one type II variation under category C.I.13 per final study report will still be requested (provided that the product information remains unaffected).
It should be noted that these requirements also apply to all non-clinical studies, including the provision of final study reports for in vitro studies.
In case the final non-clinical or clinical study report leads to consequential changes to the RMP, the MAH can include an updated RMP version as part of the type II variation regardless of whether it is submitted under category C.I.6, C.I.4, C.I.11 or C.I.13.
With regard to 'interim' non-clinical or clinical study results, the timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in RMPs unless required as part of an agreed pharmacovigilance plan. On the other hand, such results should be reported in relevant PSURs.
When interim results have been requested by the CHMP and are provided in order to address a specific post-authorisation measure (PAM), the data should be submitted in line with the requirements of the PAM procedure, unless the MAH considers that the interim data result in consequential changes to the product information and/or the RMP in which case a type II variation should be submitted instead.
With reference to analyses across studies on specific topics (e.g. a biomarker report from more than one study) for which the individual final study reports have previously been submitted, the analysis should be submitted under category C.I.4 (in case of changes to the product information), under category C.I.11 (changes limited to the Annex II conditions) or as a PAM (no changes to the product information and/or the RMP are warranted). When the analyses should be submitted as variations, one variation scope per analysis (and not per study included in the analysis) should be submitted.
Final results from an imposed non-interventional post-authorisation safety study (PASS category 1 and 2 in the RMP, and reflected in Annex II) should be submitted within 12 months of the end of data collection unless a written waiver has been granted by PRAC, as appropriate (please refer to guidance on imposed post-authorisation safety studies). Final (and also interim) results should be submitted as a variation, if the MAH considers that changes to the product information are warranted. If not, then the submission should follow the relevant Art 107q of Directive 2001/83/EC procedure (please also refer to guidance on post-authorisation safety studies).
Any pre-submission queries in this regard should be addressed to the appointed Procedure Manager.
In principle, one change to the PI supported by one set of data constitutes one assessment and subsequently one scope i.e. one type II variation.
All data/study reports provided as part of a variation must support the same changes to the SmPC. If this is not the case, i.e. some data support one change (update A), and other data support another change (update B), it will be necessary to submit separate stand-alone variations or a group of variations, as appropriate; one variation for SmPC update A including the data supporting A, and one variation for SmPC update B including the data supporting B.
In the event that some of the data/study reports proposed to be part of an application do not support any of the proposed changes to the SmPC, the reports give rise to separate variation scopes (category C.I.13 – one variation per final study report as explained under 'How should non-clinical and/or clinical study reports be provided?'), which could potentially be grouped in the same submission or may need to be removed from the proposed variation application and submitted as a separate appropriate application.
Thus, only when changes are consequential to the same supporting data, can one type II variation application propose changes to several different sections of the SmPC as well as corresponding changes to the Package Leaflet. Any additional changes to the PI that are consequential to the assessment of another set of data will have to be submitted as part of a separate variation (stand-alone or part of a grouped application to be decided on a case-by-case basis).
Some theoretical examples are being provided below to illustrate the principles explained above.
Proposed application: Provision of final clinical study reports (CSR) for 3 PK studies (studies X, Y, Z).
- If the data from the 3 CSRs support the same SmPC updates, the reports should be submitted as part of one single type II variation under category C.1.4 (scope = 'update of the SmPC based on the results from studies X, Y and Z').
- If two study reports (X, Y) support one SmPC change (update A), and the 3rd study report (Z) supports a different SmPC change, the applicant should submit one type II variation under category C.I.4 for SmPC update A and one type II variation under category C.I.4 for SmPC update B. The two variations can in this case be submitted as part of a grouped application, as it makes sense to assess the 3 PK studies together (scope = 'update A of the SmPC based on the results of studies X and Y, and update B of the SmPC based on the results of study Z').
- If two study reports (X, Y) support all proposed SmPC changes and the 3rd study report (Z) does not result in any consequential changes to the SmPC at all, the applicant should submit a grouped application including one type II variation under category C.1.4 (studies X, Y) and one type II variation under category C.I.13 (study Z). The two variations can in this case be submitted as part of a grouped application, as it makes sense to assess the 3 PK studies together (scope = 'update of the SmPC based on the results of studies X and Y. The applicant also provides study Z as a grouped variation as a common assessment of these changes is considered meaningful').
Proposed application:Provision of one CSR for study A supporting SmPC changes regarding efficacy in patient population A and overall clinical safety, and one CSR for study B supporting SmPC changes regarding efficacy in patient population B and overall clinical safety.
- In view of the fact that the efficacy data are unrelated and concern two separate patient populations, two separate assessments will need to be undertaken and two separate type II variations will be required. However, as the scopes of the two variations are both partly related to overall clinical safety, it is meaningful to assess them together and the applicant should therefore provide the two variations as part of one grouped application.
- However, in the event that the data sets would be completely unrelated - e.g. because of different safety profiles in the two patient populations due to different posology -the reports should be provided as part of two separate stand-alone type II variations; one for patient population A (efficacy and safety) and one for patient population B (efficacy and safety).
Proposed application: Update of the SmPC section 4.8 in order to add three new ADRs; 'dyspnoea' and 'chromaturia' following a review of the MAH's safety database undertaken upon request by PRAC following a PSUSA procedure,and 'Kounis syndrome' following the MAH's own signal detection.
- As the three ADRs are supported by two separate data sets the MAH should submit two variations as part of a grouped application; one type II variation under category C.I.3.b to add 'dyspnoea' and 'chromaturia', and one type II variation under category C.I.4 to add 'Kounis syndrome'. Both variations are related to clinical safety and it makes sense to assess them together hence the acceptability of the grouping.
- Provided that all non-clinical and clinical data that will be submitted as part of the application are supportive of the new claimed indication, the studies should be provided as part of the application without the need for any additional variation.
- However, in the event that e.g. one of the non-clinical studies is not supportive of the proposed extension of indication, it will need to be submitted as part of a separate variation application (stand-alone or part of a grouped application to be decided on a case by case basis).
Any pre-submission queries in this regard should be addressed to the allocated EMA procedure manager.
As of 1 February 2016, changes to the summary of the pharmacovigilance system – changes in QPPV (including contact details) and/or changes in the Pharmacovigilance Master File (PSMF) location are to be notified to the authorities through the Art 57 database only without the need for any further variation. From that date MAHs are not required to notify EMA or national competent authorities (as applicable) of changes to the QPPV or PSMF data by submitting a type IAINvariation.
Upon a change in the QPPV or location of the PMSF, the Art 57 database should be updated by the MAH immediately to allow continuous supervision by the Competent Authorities.
- News Item: Regulatory information - Green light for reliance on Article 57 database for key pharmacovigilance information on medicines for human use in Europe
- Art 57 Reporting requirements for Marketing Authorisation Holders
- Detailed Guidance on electronic submission of information on medicines
3.5. How should I submit data requested as a follow-up to a prior regulatory procedure?
Occasionally, the outcome of a regulatory procedure may require the MAH to follow-up on certain aspects in a subsequent regulatory submission. The type of submission required depends on the nature of the data requested and whether the implementation impacts the Product Information (PI) and/or the Risk Management Plan (RMP).
If the outcome of the prior regulatory procedure requests the submission of a (non-)clinical study report, this should always be submitted as a variation (unless this is a paediatric study submitted under Article 46 of the Paediatric Regulation (EC) 1901/2006). Any other requested information (e.g. cumulative safety review) should be submitted as a variation if it has impact for the PI or the RMP. In other cases, it can be accepted as a Post Authorisation Measure (PAM).
Similarly, if the prior procedure already recommends changes to the PI or the RMP, these should be submitted as variation, unless the MAH would like to provide a justification why such changes are not supported by the MAH. In the latter case, the rationale for not submitting a variation proposing the indicated PI and/or RMP changes and any requested data supporting the rationale can be submitted as a PAM. If however the data requested involves the submission of a final (non-)clinical study report, a variation should always be submitted even if no changes to the PI and/or RMP are proposed (with the exception of submissions under Article 46 of the Paediatric Regulation (EC) No 1901/2006).
The classification of the variation depends on the nature of the prior procedure the outcome of which is being implemented:
- for implementation of the outcome of a Union referral procedure, the applicable variation category is C.I.1.
- for implementation of the outcome of a PSUR, PASS protocol or PASS results procedure, the applicable variation category is C.I.3. It should be noted that PI changes resulting from PSUR data should ideally be implemented within the PSUR procedure itself; only if additional data are required to support the PI changes which cannot be submitted and assessed during the PSUR procedure, should a follow-up variation of the C.I.3 category be submitted.
- in case of a procedure under article 46 of Paediatric Regulation No (EC) 1901/2006, the applicable variation scope is C.I.3 only in case changes to the PI are proposed. In principle, it is expected that in most cases PI changes are to be proposed. In the exceptional case that no changes to the PI are proposed, a PAM procedure should be applied for (see also question How should non-clinical and/or clinical study reports be provided?)
- for the implementation of the outcome of a signal assessment, the appropriate variation category is C.I.z, as also indicated in the CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008.
- for the alignment of the PI of a generic, hybrid or biosimilar medicine to that of the reference product the applicable variation category is C.I.2 with the exception of the implementation of wording from PSUR and PASS procedures ; the applicable scope category in such cases is C.I.3.
any other prior regulatory recommendation should be implemented via: a C.I.4 variation category, if changes to the PI are proposed; a C.I.11 variation category, if changes to the conditions in Annex II of the PI or in the RMP are proposed; a C.I.13 variation category, if a final (non-)clinical study report is being submitted; a PAM, if a paediatric final study report is being submitted under the requirements of Article 46 of Paediatric Regulation 1901/2006 and in all other cases where requested data and analyses are being submitted without an impact to the PI (including Annex II) and the RMP (please also refer to question Under which procedure should I submit my PAM?).
3.6 What is considered a new or modified therapeutic indication? NEW December 2016
Applications proposing changes to the therapeutic indication aiming to extend the target population (either by modifying an existing indication(s) or by extending in a completely new indication/target disease) trigger paediatric and orphan requirements (please refer to questions 'What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?', 'Do I need to address any paediatric requirements in my type II variation application?', 'What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?' and 'Do I need to address any paediatric requirements in my extension application?' in the post-authorisation guidance for type II variations and Extension of Marketing Authorisations).
The EC Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection and the EC Guideline on a new therapeutic indication for a well-established substance provide a definition of what is considered a 'new indication'. More specifically, a new (or modified) indication is:
- a new target disease;
- different stages or severity of a disease;
- an extended target population for the same disease, e.g. based on a different age range or other intrinsic or extrinsic factors;
- a change from first-line treatment to second-line treatment (or second-line to first-line treatment), or from combination therapy to monotherapy, or from one combination therapy (e.g. in the area of cancer) to another combination;
- change from treatment to prevention or diagnosis of a disease;
- change from treatment to prevention of progression of a disease or to prevention of relapses of a disease;
- change from short-term treatment to long-term maintenance therapy in chronic disease.
However, in some particular situations a case-by-case assessment may be needed to determine whether the target population is extended. For example, the following may not be considered a new indication:
- information on the use of the medicinal product in the authorised target diseases in patients with renal or hepatic impairment;
- information on the use of the medicinal product in the authorised target diseases in pregnant women;
- for vaccines, information on the concomitant administration with other vaccines.
In addition to applications extending the target population, orphan similarity requirements are also triggered by any extension of the Marketing Authorisation (line extension, please refer to question 'What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?').
Paediatric requirements are triggered by an extension of the Marketing Authorisation (line extension) for new pharmaceutical forms and/or new routes of administration (please refer to question ' Do I need to address any paediatric requirements in my extension application?').
From a procedural point of view, extensions of indication can be submitted as type II variations or extensions of the Marketing Authorisation depending on whether the change in the target population is accompanied by other changes e.g. changes to the strength, pharmaceutical form, route of administration (please refer to question 'When will my variation application be considered a Type II variation or an Extension application?').
For extensions of the Marketing Authorisation, in case the change in the indication is only intended for the new pharmaceutical form/ strength being added, the extension of indication is covered by the scope of the MA extension application. In case the change(s) in the therapeutic indication also applies to existing presentations, the application should be presented as a grouping of a line extension(s) and C.I.6.a scope variation.
When the extension of indication is submitted as a type II variation application, the C.I.6.a scope category (i.e. addition of a new therapeutic indication or modification of an approved one) typically applies. However, not all variations under the C.I.6.a. scope category are actual extensions of indication (e.g. restrictions of an existing indication also fall under this scope category). The contrary is also the case: there are variations which aim to extend the target population but which do not affect the wording of the approved therapeutic indication in section 4.1 of the SmPC. so the variation category is not C.I.6.a but rather C.I.4 (changes in the Product Information due to new quality, preclinical, clinical or pharmacovigilance data). Ultimately, if the 'target population' is extended, the orphan and/or paediatric requirements are triggered, even though the variation may not have been submitted as a C.I.6.a 'extension of indication'.
4.1. What can be considered an editorial change and how can it be submitted as part of a type IA/IB/II variation?
The European Commission 'Variations Guidelines' 2013/C 223/01 specifies that “If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier.”. Changes that can be classified as a variation as per Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.
Editorial changes in module 3
Provided that the above condition is fulfilled, the following changes to the Module 3 may be considered editorial: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided that it can be demonstrated what is the correct reference that had been previously agreed (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.
Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.
In practice for the Agency, “that part of the dossier” can cover sections up to the fourth level of the eCTD, as follows “3.2.S.x” or “3.2.P.x”. For example, if a variation affects section 3.2.S.2.1 editorial changes can be submitted in sections from 3.2.S.2.1 to 3.2.S.2.7.
Editorial changes should always be clearly identified in the application form as following: A brief description of the editorial changes should be provided in the Precise Scope. All the editorial changes should be listed in the present/proposed table, and a justification as to why the holder considers them 'editorial' (i.e. why they should not trigger a specific variation) should be provided for each change.
In addition, the MAH should provide a declaration in the 'Precise scope and background…' section of the application form confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation submitted within which the editorial changes are being submitted.
Editorial changes in module 4 and 5
Editorial changes in module 4 and 5 are not foreseen. Please contact the appropriate pre-submission query email address (IAquery@ema.europa.eu, IBquery@ema.europa.eu) or the appointed Procedure Manager as relevant in advance of an upcoming submission.
Editorial changes to the product information in module 3.1
Formatting changes, correction of typographical errors and/or mistakes to the English Product Information or other linguistic versions of the Product Information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming variation impacting the product information.
Changes in the scientific content cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant variation as per Variations Guidelines (e.g. Type II C.I.4). If no relevant scope is available, a variation type IB C.I.z may be appropriate.
Proposed changes that may require confirmation by the rapporteur or linguistic review will only be accepted by the Agency when submitted within the scope of an upcoming variation type IB or type II under chapter C which impacts the product information.
Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required. Should there be no upcoming variation to include the editorial changes, these could also be submitted as a stand-alone IB C.I.z if they affect the English SmPC. If they affect the PIL/labelling of all language versions an Art. 61(3) notification can be submitted. If other languages are affected and in case no variation affecting the product information is upcoming, the applicants are advised to contact the Agency to discuss how to handle these necessary changes.
The MAH should liaise with the Agency without delay if the mistake concerns an incorrect or missing important information (e.g. contra-indication or adverse event) that could affect the safe and effective use of the medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).
The editorial changes should be clearly identified in the application form as editorial changes. A brief description of the editorial changes should be provided in the precise scope of the application form. Furthermore, editorial changes should be presented in the present/proposed table or provided as a separate Annex. A statement confirming that the proposed editorial change(s) do(es) not change the content of the previously approved Product information should be provided.
Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency in advance of the planned submission using the appropriate pre-submission query email address IAquery@ema.europa.eu, IBquery@ema.europa.eu or through the appointed Procedure Manager, as appropriate.
- Commission Regulation (EC) No 1234/2008 (OJ L334 of 12 December 2008)
- Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products
- 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
- CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008