1. Variations regulation – an Industry experience
12 April 2011
Janssen Research & Development
Fiona Reekie, Director, Global Regulatory Affairs
Janssen Pharmaceutical Companies of Johnson & Johnson

2. Disclaimer
The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Trademarks are the property of their respective owners.
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

3. Variations regulation – remarks from the Industry
What are the experiences after one year of the Variations Regulation?
Has the planning and management of Variations improved?
Examples from the practice - does it work?
Planning the ‘annual’ report
Type IB by default
Grouping
Fees
During this presentation I will share with you some reflections on
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

4. Reminders Type IA (Minor)
‘…has only minimal impact, or no impact at all, on the quality, safety or efficacy…’
Implement then notify (ie, do & tell)
Type IAIN: Those that for the continuous supervision of the medicinal products concerned should be notified immediately after implementation, eg, change of address of MAH
Type IA: those that should be notified within 12 month following implementation (periodic report)
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

5. Submit variations only on dossier content change!
Reminders
Type II (Major)
Not an extension and which may have a significant impact on the quality, safety or efficacy
Type IB (Default )
Variations not explicitly recognized as Type IA, Type II or Extensions
Type IA ≠ Type II ≠ Extensions ≠
Type IB by default
Submit variations only on dossier content change!
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

6. How has it been?
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

7. EMA & CMDh guidance Guidance regularly updated
providing clarification as experience grows
Dec 2009
Apr 2011
EMA Post-Authorisation Procedural Advice
Rev. 14
Rev. 18
CMDh BPGs for the submission & processing
of variations in the MRP
Rev. 6
Rev. 12
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

8. CMDh recommendations for classification of unforeseen variations according to Art. 5
Art. 5 clarification (BPG Rev. 9)
Requests will be considered invalid where
Covered by the classification guide
Recommendation has already been issued
Should clearly be classified as Type IB by default
If condition for a Type IA not met is ‘default’ Type IB not unforeseen
Unforeseen ≠ z
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

9. CMDh recommendations for classification of unforeseen variations according to Art. 5
31 Recommendations published
17 Type IBs
7 Type IIs
1 Art. 61(3) notification
1 None (to be considered on a National Level)
1 No classification recommended
1 No change necessary
3 Type IAs
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

10. CMDh recommendations for classification of unforeseen variations according to Art. 5
Section of
Classificn
guideline
Proposed
Classificn
Proposed
conditions
Summary of proposed change
Changes to the suppliers of excipients without a TSE risk and without changing any of the specifications. The current excipients suppliers are only specified in 3.2.P.4.1 section on the Certificate of Analysis of the excipients
No change
necessary
No change necessary
N/A
Change in the name of a supplier of a packaging component. If the information is not needed in the dossier CMDh recommends deletion of this information.
B.II.e.7 a) IA
N/A
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

11. CMDh recommendations for classification of unforeseen variations according to Art. 5
Section of
Classificn
guideline
Proposed
Classificn
Proposed
conditions
Summary of proposed change
Change in the specification parameters and/or limits of the finished product to more accurately describe the appearance of the drug product.
The change is not a result of any unexpected events arising during manufacture or testing of the drug product.
B.II.d.1.z IA
Update of the dossier to comply with the provisions of a general monograph for the test of a finished product of the Ph.Eur. – Tightening of specification limits
B.II.d.1.a IA
N/A
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

12. Classification guideline
No major problems to share
The variation classification guideline seems to be straight forward
But…
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

13. Classification guideline
Large molecule A - change in reference standard data
Change not listed in classification guideline
Choose the most appropriate category to include in the application form then choose ‘z) Other variation’ X X
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

14. Classification guideline
Product X
Minor change to the sampling procedure for gas chromatography of an excipient
No validation required to support change
MAH proposed ‘B.II.c.2 (a) Minor change to an approved test procedure’ Type IA
RMS advised ‘B.II.c.2 (d) Other changes to a test procedure (including replacement or addition)’ Type IB
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

15. Classification guideline
MAH X X
7 June 2010
RMS X
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

16. Classification guideline
Product Y
Minor editorial amendments to the package insert and SmPC & update frequencies of some adverse events (Sect. 4.8)
RMS advised C.I.z Changes (Safety/Efficacy) to Human and Veterinary Medicinal Products ‘Other variation’
Type IB variation if no additional data
Type II variation if additional data
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

17. Classification guideline
Product Y (contd)
Submitted as IB, requested to change to II, then agreed IB X X
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

18. Application form Completing p3:
Grouped variations within one MA (explanatory note p8)
MRP –Do we need to list all Member States MAs separately?
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

19. Application form Or prepare a Country-specific table for each CA?
NL: WonderPill A 10mg
<INN>
Tablet
10 mg
PharmaComp
NL: RVG 12345
NL/H/0111/001/IB/033/G
NL: WonderPill A 20mg
<INN>
Tablet
20 mg
PharmaComp
NL: RVG 12346
NL/H/0111/002/IB/033/G
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

20. Grouping Approach to variations becoming more strategic Examples:
Product A (MRP): CMC Module 3 harmonization as a single grouping of 13 variations
1 Type II for harmonization, 8 Type 1As for individual changes & 3 Type IB, IAIN
Products B, C, D & E: DDPS update (DDPS already assessed for another med product ‘of the same MAH’
8 variations: 4 x IAIN and 4x IA
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

21. Grouping Product B (MRP): a single grouping of 4 X IAIN variations
DDPS update (all CMS) + MAH change of address (2CMS)+ MAH change of name (1CMS)
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

22. Challenges High rate of rejections of Type IAs
MHRA published rejection rate ~30%
Poor understanding or inadequate training?
Lack of attention to detail
Identifying when a change does not need submission
Numbering of variations
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

23. Challenges Type IA(IN) variations during repeat MRP procedures
Some CAs advise to submit during repeat-use MRP as these are immediate notifications, others advise to wait until the end of the procedure
A CMD(h) agreement is needed
Classification differences between CAs
Type IB in one country Type II in another
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

24. Challenges Inconsistencies
Type IA IN - comment raised the variation submitted late versus the implementation date. Other products did not receive this comment although they were around the same timeframe.
Timely changes in relation to CoPPs
IAIN – sometimes takes time to get the documentation
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

25. Challenges Implementation date – submission in advance for CoPPs
Some CAs accept submission in advance of implementation
Grouping proposal
Lack of response from RMS
Variations submitted as separate submissions
Delay while acceptability of grouping is discussed encourages individual submissions
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

26. Challenges Flexibility to report within 12 months useful
Ensure that there is a suitable change management system in place to handle periodic notification of Type IA changes
Delays – overload of the system?
Type IB delay
4 weeks between submission and validation letter
Difficult to plan
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

27. Tips for success
Ensure suitably qualified & trained staff (familiar with the latest published guidance)
Before submission conduct quality control checks on content of Type IA notifications
Ensure application form completed, in accordance with the relevant guidance
Specify the correct change code(s)
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

28. Tips for success Include implementation date
Complete the checklists correctly
Ensure relevant conditions & documentation requirements are fully met
If a documentation requirement is not applicable, use ‘NA’ instead of a tick and give an explanation as to its non- applicability
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

29. Tips for success Link to MHRA Variations Advice
If notification contains a number of different changes under the same general change code (high level), ensure that separate check lists supplied for each specific change code
Review latest Q&A on EMA/CMDh websites
Link to MHRA Variations Advice
Link to BfArM Variations Advice
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

30. Suggestions for improvement
Accept submission of Type IAs pre implementation
Provide approval letters
Required for use in some International markets
Reduce timelines for Art. 5 recommendations
Improve consistency across CAs
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

31. Suggestions for improvement
Be more flexible on ‘umbrella’ changes
Regular update of Q&As
Invite MAHs to contribute
Expand Q&As on groupings
Expand regulation to Nationals as soon as possible
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

32. Conclusions Mixed Mixed Challenging Yes Yes More expensive?
What are the experiences after one year of the Variations Regulation?
Has the planning and management of Variations improved?
Examples from the practice - does it work?
Planning the annual report
Type IB by default
Grouping
Fees
Mixed
Mixed
Challenging
Yes
Yes
More expensive?
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

33. References Application form and explanatory notes
Link to form
Art 5 recommendations
EMA post authorisation guidance
Link to EMA guidance
CMDh BPG
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

34. Abbreviations
BfArM: Bundesinstitut für Arzneimittel und Medizinprodukte
BPG: Best Practice Guide
CA: Competent Authority
CoPP: Certificate of Pharmaceutical Product
EMA: European Medicines Agency
MHRA: Medicines and Healthcare products Regulatory Agency
MRP: Mutual Recognition Procedure
SmPC: Summary of Product Characteristics
GLOBAL REGULATORY AFFAIRS | Variations Industry Remarks

35. Questions