Swissmedic Swiss Agency for Therapeutic Products Hallerstrasse 7 CH-3000 Bern Workshop 3 – Life Cycle Management 2nd Follow-up Information Meeting with Workshops – Step 3 Damian Schöni, Céline Jurt Kuster, Dr. Stephan Järmann, Sibylle Stettler 16 th March 2011

2 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

3 Introduction (I) What do you expect from this workshop?

4 Introduction (II) Goals of the workshop  Learn about Swissmedic's LCM requirements to submit eCTD sequences over the whole product lifecycle  Understand the DO'S and DON'TS to create proper eCTD sequences by means of case studies  Use the opportunity to discuss your questions to benefit your daily work

5 Introduction (III) Time limitation!  Focus on two of the four following topics: Case 1:Application types Step 3 (§13 TPA, PSUR, others) Case 2:Variations Case 3:Baselines Case 4:Technical Validation  Preferences of the audience?

6 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

7 Definition of LCM (I) Swissmedic’s requirements for eCTD submissions (see Guidance for Industry, chapter 5)  Life Cycle Management at the “Drug Product” layer (eCTD application):  Proper start of Life Cycle (0000)

8 Definition of LCM (II)  Life Cycle management at the submission layer (eCTD-sequence):  Proper use of metadata (e.g. sequence number; related sequence, application type)  Life Cycle Management at the document layer (eCTD leaf):  Proper use of operators  Life Cycle Management of specific documents

9 Swissmedic view of the drug product Regulatory activity (application type) eCTD sequence (submission) Product trade name eCTD repository Swissmedic

10 eCTD Sequence: Envelope with Metadata Life Cycle related metadata

eCTD Sequence: Document with Operators (I) 11 Documents with operators

12 eCTD Sequence: Document with Operators (II) NewThis is a file with no relationship to an existing file in the eCTD (e.g. all documents in the initial MAA should be new; certain documents in the Swiss Module 1 have no life cycle and are always new) ReplaceDocuments replacing an existing file in eCTD submission:  A modified document should be a replacement  Replaces a previously submitted new, appended or replacement document

13 eCTD Sequence: Document with Operators (III) AppendAppended files contain supplementary information to a currently existing file in the eCTD  Document to be read in conjunction with a previously submitted document (do not append a file to an appended file)  e.g. Clinical Overview for an additional indication DeleteDelete a document from the eCTD and no new document is submitted Makes the previously submitted document obsolete (e.g. withdrawal of a file related to a rejected regulatory activity; withdrawal of a file related to a manufacturer that is no longer involved in the manufacture of a product)

14 Definition of LCM Questions 1.Why is LCM important? 2.What are the possible benefits of LCM?  Discuss with your neighbour(s) Time: 5 minutes

15 Benefits of Life Cycle Management (I) Commercialisation Initial Marketing Authorisation Maintenance Development Variations, PSURs, Renewals

16 Benefits of Life Cycle Management (II) LCM offers traceability and transparency  version control: proper version of documents  which version of a document belongs to which submission  changes in submissions and documents: LCM places documents in the context of the previous submissions  easier to find and compare changes  current view: The current eCTD sequence represents the current status of the product (all documents in their current versions)  no old/double or wrong documents

17 Benefits of Life Cycle Management (III) Current view (status of the product) blue = last submissions Document history

18 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

19 LCM Applications according to §13 TPA (I) Switching between paragraph 13 TPA submissions and Swiss-only submissions (Swiss eCTD lifecycle) Examples  NA NAS § 13 TPA  Notification quality (e.g. Change of the primary packaging material)  Variation regulatory (e.g. Change in the name of the product)  NA NGF § 13 TPA  How to structure the lifecycle?

20 LCM Applications according to §13 TPA (II) Structure of the lifecycle Submissions according to “§ 13 TPA” Submissions “Swiss only”

21 LCM Applications according to §13 TPA (III) Conclusions  It is possible to alternate between paragraph 13 TPA submissions and Swiss-only submissions  Document operators have to be adapted to the lifecycle within the Swiss eCTD

22 LCM with PSUR (I)  PSUR is always a stand alone application  No combination with a variation of the product information (ZL304)  In case of a variation of the product information on the basis of the PSUR:  2 different forms („PSUR“ & „Application for Authorisation / Variation“)  2 different sequences  PSUR has to be submitted only once (in Chapter 5.3.6)

23 Two forms PSUR is always a stand alone application LCM with PSUR (II)

LCM with PSUR (III) 24 Example of the Lifecycle (Envelope)  Sequence 0003: PSUR  Sequence 0004: Variation of the product information

LCM with PSUR (IV) 25 Sequence 0003: PSUR

LCM with PSUR (V) Sequence 0004: Variation of the product information 26 Hyperlinking to PSUR (5.3.6) in Sequence 0003

27 Other applications Step 3: Prolongation Lifecycle Management  Once eCTD always eCTD  Follow-up applications must be submitted in eCTD format  Example: Prolongation No paper submission allowed!

28 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

29 LCM with Variations (I) Overview variation types  Variations requiring a notification procedure (ZL301)  Variations requiring authorisation incl. scientific review (ZL302)  Variations requiring authorisation without scientific review (ZL303)  Variations requiring authorisation of the product information incl. scientific review (mainly of preclinical or clinical documentation) (ZL304)

30 LCM with Variations (II) LCM has two aspects  Technical point of view  Content/regulatory point of view

31 LCM with Variations (III) Most important LCM topics 1.Collective Application (Variation which refers to more than one authorisation number; Sammelgesuch / demande groupée) 2.Multiple simultaneously submitted variations (several variations to one or more marketing authorisation numbers; Mehrfachgesuche / demande multiple) 3.Sequential Variation / Sequential Variation requiring notification (Folgeänderung, Folgemeldung / modification consecutive, annonce consécutive) 4.Handling of eCTD sequences in case of a rejected or withdrawn variation (consolidation sequence)

1. Collective Applications (I) Application which refers to more than one drug product (collective application / Sammelgesuch / demande groupée)  E.g. for collective application: change of the MAH’s address for several products at the same time, variation of section drug substance  One eCTD sequence per eCTD life cycle has to be submitted  In the envelope of a sequence all related authorisation numbers within the life cycle should be indicated.  In case of a collective application for several eCTD lifecycles: Confirmation that the documentation is identical for all life cycles submitted 32

1. Collective Applications (II) Collective Application: All related Authorisation Numbers should be indicated For every eCTD lifecycle the envelope has to indicate all related authorisation numbers Reason: The references to related products are easy visible for administration and review inside Swissmedic 33

1. Collective Applications (III) 34 Example for collective application within one life cycle Multiple simultaneously submitted variations: 2 new manufacturers

1. Collective Applications (IV) Two different life cycles: The same form Please be aware that the operators of both documents may be different:  depending on the individual Life Cycle of the product  Depending on the Life Cycle of the documents in Module 1

2. Multiple simultaneously submitted variations Several variations to one or more marketing authorisation numbers (Mehrfachgesuche, demande multiple)  One eCTD sequence per eCTD life cycle has to be submitted  Variations requiring notification (ZL301) and Variations of the product information requiring authorisation (ZL304): one sequence per variation has to be submitted  Variations requiring authorisation (ZL302): More than one variation can be submitted within one sequence 36

2. Multiple simultaneously submitted variations 37 Example: Variations requiring authorisation (ZL302) Multiple simultaneously submitted variations (one for capsules and one for oral solution) Reason: Better accessability of documentation during review (especially Quality Review)

3. Sequential Variation Submission of a sequential variation or sequential variation requiring notification (Folgeänderung, Folgemeldung; modification consecutive, annonce consécutive)  The submission of a sequential variation/notification should be included in the same sequence as the related variation/notification (see also form variation requiring authorisation or form variation requiring notification) 38

4. Rejected or partially rejected application (I) Handling of eCTD sequences in case of a rejected or partially rejected application  Rejected variations should not appear in the current view  If a submission is withdrawn or rejected, a consolidation sequence should be submitted to reinstall an updated (i.e. corrected) current view by removing eCTD documents associated with the rejected/withdrawn variation (see also in Q&A, Q8-7)  A consolidation sequence is usually submitted for Module 3 39

4. Rejected or partially rejected application (II) 40 Example of consolidation sequence (0003) after partially rejected application (variation sequence 0002): Reason:Rebuild the current status (current view) of the product in the Life Cycle (especially Module 3) Be aware that Swissmedic may contact you for a consolidation sequence if there are major Life Cycle issues!

41 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

LCM with Baseline Submissions (I) Definition of a Baseline  A baseline submission is reformatted documentation of information previously submitted in paper  Usually for Modules 1 and 3  Required documents for Module 1 see Guidance for Industry, chapter 6  Submitted as a separate submission (envelope attribute application type: reformat) 42

43 LCM with Baseline Submissions (II) Questions about Baseline Submissions  Is the submission of a baseline recommended or mandatory?  What are the possibilities and benefits of a baseline submission?  When is the submission of a baseline allowed?  Which problems may occur with a partial baseline or no baseline in the lifecycle of a product?  Example on FlipChart  Discuss with your neighbour(s)  Time: 5 minutes

LCM with Baseline Submissions (III) Is the submission of a baseline recommended or mandatory?  See Guidance for Industry Version 1.2, Chapter 6 44

LCM with Baseline Submissions (IV) What are the possibilities of a baseline submission?  See Guidance for Industry Version 1.2, Chapter 6 Swissmedic recommends option 3 45

LCM with Baseline Submissions (V) What are the benefits of a baseline submission?  At a given point in time the lifecycle is fully in electronic format  Good overview on product history  The review becomes easier 46

LCM with Baseline Submissions (VI) Additional advantages for Option 3: Partial baseline of quality  Only 1 sequence to be technically validated  Best ratio benefit/work load Disadvantages of Option 5: No baseline at all  No overview on currently valid documents  Time-consuming review of quality variations  Paper documents still needed for review  Lifecycle starts “out of the blue” 47

LCM with Baseline Submissions (VII) When is the submission of a baseline allowed?  NOT within a ongoing application  Preferred option: At the beginning of the transition from paper to electronic as sequence 0000  For products with anticipated variations of M3  Before or at the same time as a variation (Module 3)  Sometimes a consolidation sequence will be necessary  Choose the time point carefully and balance pros and cons 48

LCM with Baseline Submissions (VIII) Consolidation sequence Baseline 49

LCM with several Baseline Submissions Baseline submission including Regulatory Activity B Baseline submission following regulatory Activity A Regulatory Activity C 50

LCM with Baseline Submissions (IX) Which problems may occur with a partial baseline or no baseline in the lifecycle of a product? Example: No Baseline  Sequence 0000 New Indication (Module 1 and 5)  Sequence 0001Answer to Content validation  Sequence 0002Answer to List of Question  Sequence 0003Answer to Preliminary Decision Variation requiring a notification procedure Quality  Sequence 0004How to build Sequence 0004? 51

52 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

53 Technical Validation Technical validation and content validation Technical validation of the LCM Technical LCM errors Combined technical / regulatory LCM issues Conclusions LCM Validation

54 Technical validation and content validation e.g. Initial Marketing Application Technical LCM issues (Division: "Document Management") Combined technical / regulatory LCM issues (Division: "Case Management") Two types of validation within Swissmedic, conducted by different Divisions

55 Technical Validation Technical validation and content validation Technical validation of the LCM Technical LCM errors Combined technical / regulatory LCM issues Conclusions LCM Validation

Technical validation of the LCM (I) 56 Requirements for Applicants  Swissmedic requires the applicant to submit technically valid eCTD sequences together with the form “technical validation” (previous validation of the submission is required) Reminder  To check for LCM errors, the technical validation has to be performed together with the previous submissions (≠ stand alone validation of the eCTD sequence)

Technical validation of the LCM (II) 57  Swissmedic performs the technical validation within 10 working days  The applicant gets feedback from Swissmedic about the quality of the submission and possible corrective actions:  reject (replacement sequence, validation clock not started)  correction in subsequent submission  recommended or no corrections Reminder

Technical validation of the LCM (III) The validation process within Swissmedic  Life Cycle errors are often only visible when uploaded in the review tool (in relation to the previous submissions)  Life Cycle errors may be medium/low validation errors but may lead to rejection or request for re-submission of the eCTD sequence! 58

59 Technical Validation Technical validation and content validation Technical validation of the LCM Technical LCM errors Combined technical / regulatory LCM issues Conclusions LCM Validation

Technical LCM errors (I) Ex. 1 of technical LCM errors: Errors in the envelope A20 (Sequence number has not already been used):  Replacement = same sequence number  Correction in subsequent sequence (e.g. “Beanstandung formale Kontrolle” = new sequence number) Only one occurence of this sequence number in the life cycle! 60

Technical LCM errors (II) Example 2 of technical LCM error: Errors with LCM operators B9 (The life cycle operators “append”, “replace” or “delete” refer to a valid document in a previous submission)  No document history. Versioning of document not correct! Reference to replaced document is not correct! (Only replaced document should be visible!) LCM operators: New Replace 61

Technical LCM errors (III) Example 3 of technical LCM errors: C4 (The envelope-referenced sequence entry is valid): Baseline Submission has no related eCTD sequence (they represent a regulatory starting point!)  Wrong metadata can only be corrected with a replacement (envelope contains no Life Cycle Operators!) Should be "none" 62

63 Technical Validation Technical validation and content validation Technical validation of the LCM Technical LCM errors Combined technical / regulatory LCM issues Conclusions LCM Validation

Example 1 of technical / regulatory issues: Metadata Combined techn. / reg. LCM issues (I) Should be "reformat„ Should be "none" Should be "0000" 64

Combined techn. / reg. LCM issues (II) Cover Letter has no lifecycle!  The cover letter does not have a life cycle, the operator is always “new” (exception: if it needed to be replaced since it contained an error; annexes to the cover letter may have a life cycle, e.g. tracking table)  Attention: There are further documents with no life cycle in Module 1! Details: Please see additional list Example 2: Wrong LCM operator (especially Module 1) 65

Combined techn. / reg. LCM issues (III) Example 3: Wrong Galenic Form Name References between folders are missing  Note that the name of the galenic form must stay the same over the life cycle to ensure the reference in the life cycle 66

Combined techn. / reg. LCM issues (IV) Example 4: New Galenic Form in Module 1 Interruption of document history when an additional galenic form is introduced into Swiss Module 1 (use of common folder)  Shift of documents from galenic form folder to common folder  Documents that are shifted will receive the operator "delete" in the galenic form folder, and the operator "new" in the common folder Potentially relevant documents: see additional list 67

68 Combined techn. / reg. LCM issues (V) Shift from galenic form folder (operation „delete“) to the common folder (operation „new“) Example 4: New Galenic Form in Module 1

69 Technical Validation Technical validation and content validation Technical validation of the LCM Technical LCM errors Combined technical / regulatory LCM issues Conclusions LCM Validation

70 Conclusions LCM Validation (I)  Swissmedic checks the correctness of the Life Cycle Management by means of technical validation and content validation  Technical Life Cycle errors may only be detected if the validation of the current eCTD sequence is conducted together with the previous eCTD sequences of the product

71 Conclusions LCM Validation (II) Most important technical and technical / regulatory LCM issues  Metadata in the envelope (especially values within “sequence number” and “referenced sequence number”)  LCM operators of documents (e.g. replacement without preceding document; wrong operators especially in documents without LCM in Module 1)  The addition of galenic forms in Module 1 may lead to interruptions of document histories (delete documents in galenic form folder with operator "delete", add documents with operator “new” in common folder)

72 Overview 1.Introduction 2.Definition of LCM 3.Case 1: Application types Step 3 (§13 TPA, PSUR, others) 4.Case 2: Variations 5.Case 3: Baselines 6.Case 4: Technical Validation 7.Conclusions and Feedback

73 Take home messages (I)  LCM offers traceability and transparency of the changes of a submission in relation to the previous submissions and enables display of the current status of a product  §13 TPA: It is possible to alternate between paragraph 13 TPA submissions and Swiss-only submissions with a consolidation sequence. BUT: Document operators have to be adapted to the lifecycle within the Swiss eCTD!  A PSUR is always a stand alone application. The combination with a variation of the product information (ZL304) is not allowed (2 different sequences necessary). Nevertheless, the PSUR has to be submitted only once (in Chapter 5.3.6)

74 Take home messages (II)  Variations: Not all types of variations can be submitted within one eCTD sequence. Please consult the guidance or the Q&A first. In case of doubt please contact:  A baseline submission is reformatted documentation of information previously submitted in paper (separate submission). The time point to submit a baseline should be chosen carefully. The pros and cons and the importance of anticipation of future applications must be evaluated.

75 Take home messages (III)  To detect LCM errors, the technical validation of eCTD submissions must be conducted together with the previous submissions. Errors most frequently occur due to incorrect envelope metadata and improper use of LCM operators  Be aware that Swissmedic may contact you for a consolidation sequence if there are major Life Cycle issues in your product!

76 Feedback Did we meet your expectations?