Handling ongoing variations concerning same document LCM M2 and Ongoing variations 090416 Handling ongoing variations concerning same document Hans van Bruggen c.s. www.ectdconsultancy.com hbruggen@ectdconsultancy.com www.eCTDconsultancy.com

Options on a document level - 1 LCM M2 and Ongoing variations 090416 Options on a document level - 1 Separate documents, each including one change First one replaces existing document, next one is new 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Options on a document level - 2 LCM M2 and Ongoing variations 090416 Options on a document level - 2 Same document in both sequences, including both changes First one replaces existing document, which is being replace by the next one To be addressed in the cover letter If both are accepted, no consolidation required If one is not accepted, withdraw the submission and replace all its documents by the approvable documents 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Options on a document level - 3 LCM M2 and Ongoing variations 090416 Options on a document level - 3 Separate documents, first one contains 1 change, next one both First one replaces existing document, which is being replace by the next one To be addressed in the cover letter If both are accepted, no consolidation required If one is not accepted, withdraw the submission all replace its documents by its previous documents 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 Cumulative Current Initial MAA m1 m2 m3 m1 m2 m3 m1 m2 m3 m3’ m3’’ new new new new new 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 Cumulative Current Initial MAA Type II Quality Type I Quality Type II Quality m1 m2 m3 m1 m2 m3 m1 m2 m3 m3’ m3’’ m1 m3 new new replace replace replace replace 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 Cumulative Current Initial MAA Type II Quality Type I Quality Type II Quality m1 m2 m3 m1 m2 m3 m1 m2 m3 m3’ m3’’ m1 m3 m1 m3 new new new replace replace new replace replace 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations Cumulative Current Initial MAA Type II Quality Type I Quality 090416 Type II Quality m1 m2 m3 m1 m2 m3 m1 m2 m3 m3’ m3’’ m1 m3 m1 m3 m1 m2 m3 new new new new replace replace replace new Replace + delete replace new replace replace 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations Current Initial MAA Type II Quality Type I Quality m1 m2 m3 Type II Quality new replace replace + delete 090416 Consolidation m1 m2 m3 m1 m2 m3 m3’ m3’’ m1 m3 m1 m3 m1 new new new new replace replace new replace replace + delete replace 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Lifecycle management of Module 2 LCM M2 and Ongoing variations 090416 Lifecycle management of Module 2 Hans van Bruggen c.s. www.ectdconsultancy.com hbruggen@ectdconsultancy.com www.eCTDconsultancy.com

Current handling of M2 in paper LCM M2 and Ongoing variations 090416 Current handling of M2 in paper Initial MAA corresponds to eCTD guidelines M2 documents are not always updated during Q&A following the initial MAA M2 documents are not necessary for Type I variations (CMC) M2 not always updated during Q&A following Type II or Line extensions The maintenance of M2 overviews and M3-5 documents is out of synch 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Existing Regulatory Guidance LCM M2 and Ongoing variations 090416 Existing Regulatory Guidance ICH M4 on Organization EC Directive 2001/83/EC updated by 2003/63/EC EC Regulation 2003/1084/EC 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 ICH M4 on Organization 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

EC Directive 2001/83/EC updated by 2003/63/EC LCM M2 and Ongoing variations 090416 EC Directive 2001/83/EC updated by 2003/63/EC 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 EC Regulation 2003/1084/EC 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Summary of legislation LCM M2 and Ongoing variations 090416 Summary of legislation ICH M4 states that granularity should not be changed over lifecycle This allows document lifecycle - replacement of documents by updated documents – within the eCTD lifecycle But, the Regulatory Legislation suggests that updating of the overviews would rarely be done because Initial MAA: Experts are required to provide a critical analysis of Module 3, 4 and 5 Type II Variation: Must be an addendum or update of to initial overviews providing a critical analysis of the variation No QOS involved in Type I variation 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

LCM M2 and Ongoing variations 090416 Concluding remarks There is no clear good or bad method. Companies are following a variety of methods Agencies are accepting the variety of methods without consistent preference CTD and eCTD imply using an integrated approach (meaning only one ‘set’ of M2 documents Current legislation on variations tends to the non-integrated approach Using Addenda is a benefit to the affiliate office Europe and US is not expected the M2 overviews to be updated Non-integrated approach requires proper titles and file names 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Example Lifecycle Clinical Overview LCM M2 and Ongoing variations 090416 Example Lifecycle Clinical Overview Initial MAA: Clinical Overview on Mild to Severe Headache Question: Insufficient data to support mild headache Response: Agree Only Moderate to Severe Headache Approval on Moderate to severe headache Safety Variation II: Better safety profile on longer duration of exposure data Type II: Bone Pain New Information in Clin Overview is not necessarily reflected in label New addendum or Replacement update 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Current views for non-integrated vs integrated LCM M2 and Ongoing variations 090416 Current views for non-integrated vs integrated Depends on how a document is written Non-integrated: each Overview is New each time. Content is not replaced or refined Integrated: each Overview is updated and replaced each time. Content is replaced or refined 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Proposal for Modules 2.4 and 2.6 LCM M2 and Ongoing variations 090416 Proposal for Modules 2.4 and 2.6 2.4 Integrated if the risk-benefit evaluation includes review of the entire exposure 2.6.1 Integrated approach 2.6.2+3 pharmacology per indication 2.6.4+5 PK per formulation or route 2.6.6+7 Toxicology might be by replacements or addenda There is no clear good or bad method. Companies are following a variety of methods Agencies are accepting the variety of methods without consistent preference CTD and eCTD imply using an integrated approach (meaning only one ‘set’ of M2 documents Current legislation on variations tends to the non-integrated approach Using Addenda is a benefit to the affiliate office Europe (and US) is not expecting the M2 overviews to be updated Following the non-integrated approach will require updates to the eCTD Titles and file names Integrated approach required for renewals and repeat use MRP 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Proposal for Modules 2.5 and 2.7 LCM M2 and Ongoing variations 090416 Proposal for Modules 2.5 and 2.7 2.5 either as New additional document if risk-benefit relates solely to new information Replaced if the risk-benefit evaluation includes review of the entire exposure 2.7.1 per original and additional formulation(s) 2.7.2 per additional indication or additional PK data 2.7.3 per indication by eCTD guidance 2.7.4 might follow an integrated approach if the safety is to be captured as a whole or addenda for dedicated subjects 2.7.5 CSE will be new with each indication 2.7.6 See next slide There is no clear good or bad method. Companies are following a variety of methods Agencies are accepting the variety of methods without consistent preference CTD and eCTD imply using an integrated approach (meaning only one ‘set’ of M2 documents Current legislation on variations tends to the non-integrated approach Using Addenda is a benefit to the affiliate office Europe (and US) is not expecting the M2 overviews to be updated Following the non-integrated approach will require updates to the eCTD Titles and file names Integrated approach required for renewals and repeat use MRP 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com

Organization of Module 2.7.6 LCM M2 and Ongoing variations 090416 Organization of Module 2.7.6 Separate cumulative list of clinical studies and separate synopses Create M5.2 only once reference it twice in an eCTD Create each synopses only once reference it twice in an eCTD For legacy CSRs, the synopsis in the report should be copied to a separate file for inclusion in 2.7.6 090416 LCM M2 and Ongoing variations www.eCTDconsultancy.com