Post-Notice Of Compliance Changes

1. Post-Notice of Compliance (NOC) Changes Presentation to CAPRA Post-Notice Of Compliance Changes

2. Outline • Overview of the “Post-NOC Changes” Project • Background • “How we got here’ • Summary of concerns with current status • Proposed Resolution: Key Elements • Overview of New Guidance • Content and structure • Sample draft of new criteria for categorization of changes • Implementation Options • Next Steps

3. Post-NOC Changes Project • Project Objectives: • review how post-NOC changes are managed by examining existing regulatory authorities, policies, guidances and practices of Health Canada and other regulatory agencies • develop proposal to address issues

4. Post-NOC Changes Project • Working group formed with representation from: • Therapeutic Products Directorate (Project Lead) • Biologics and Genetic Therapies Directorate • Veterinary Drugs Directorate • Marketed Health Products Directorate • Inspectorate

5. Post-NOC Changes Project • Issue identification/analysis shows that existing Policies and Guidances regarding post-NOC changes • lack clarity and detail with respect to classification of a change and documentation needed to support that change • may not conform to modern risk management principles • may not be harmonized with international practices • may not be supported by the Food and Drug Regulations

6. Post-NOC Changes Project • Many of these concerns have been identified through: • feedback from industry (by direct reviewer contact, bilateral meetings, initiatives such as Good Guidance Practices) • feedback from internal Health Canada stakeholders (review & supporting bureaux/ Centres)

7. How We Got Here • Underlying Principles: • Any change to a drug may impact the quality, safety and/or efficacy of that drug product • Any change to the drug product information (labelling) may impact the safe and effective use of that drug product

8. How We Got Here • Available tools to manage this risk: • Legislative Instruments • Food and Drugs Act and Food and Drug Regulations • Non-Legislative Instruments • Policies and Guidance

9. Food and Drug Regulations • Regulatory basis in Part C of the Food and Drug Regulations • Division 1: C.01.014.5 - annual notification confirming that “information previously supplied…is correct” • Compilation of all Level 3 changes to be filed with the annual DIN notification • Division 8: C.08.003 - “if any of the matters specified….are significantly different..” • Significant changes require a supplement to the New Drug Submission

10. Policies and Guidances • Information Letter 739 (1988) which introduced “Notifiable Changes” • New Drug: Sufficient Time policy (1991) • Extension of Expiration Dates (1991) • Changes to Marketed New Drug Products policy (1994) • Stability Requirements for Changes to Marketed New Drugs (1994) • Changes in Product-Specific Facility Information (revised in 2004) • New Drug: Sufficient Time notice (2005)

11. Focus on Major Players

12. Sufficient Time Policy • New Drug: Sufficient Time policy (1991): • Introduced to “expedite the review process and reduce the backlog of New Drug Submissions” • certain changes no longer required prior approval after 7 years of market experience

13. Sufficient Time Policy • New Drug: Sufficient Time Notice (2005): • introduced because a “number of regulatory and submission issues subsequent to 1991 require clarification, and have necessitated the review of the original policy” • intended as an interim measure only

14. The “Notifiable Change” • Introduced in Information Letter 739 (1988): • “….a portion of supplemental submissions filed by manufacturers relate to changes that are of little significance from a safety and efficacy standpoint…” • “…all manufacturers achieve a high degree of compliance for certain types of changes contained in supplemental submissions. These changes do require notification but may not require the filing of a supplemental new drug submission…”

15. The “Notifiable Change” • “Notification” would constitute: • “submission by the manufacturer, prior to the institution of a change, of information related to the change and the scientific justification for the change”; • “an audit of the information by Branch officials”; • “an increase in the inspection emphasis related to the change”

16. The “Notifiable Change” • What it has become… • NCs are rarely ever allowed to default, as regulatory scrutiny is considered imperative • NOL or NSN issued • 869 NCs received in TPD alone in 2005 (compared to 567 NCs received in 2000) • 350 NCs received in BGTD in 2005 (compared to 212 in 2000) • some changes now handled as NCs really are “significant” changes as per C.08.003 • not every change now handled as an NC requires prior review and approval

17. Changes to Marketed New Drug Products Policy • Changes to Marketed New Drug Products (1994) • reflected “the regulatory amendments to C.08.003 proposed in Schedule 733”. • introduced to “reduce the number of instances where a S/NDS must be filed, and to provide an updated interpretation of the requirements of C.08.003.” • Defines 4 levels of change based on the potential impact on safety and efficacy • placed Notifiable Changes within the tiered structure

18. Schedule 733 • Regulatory proposal Schedule 733 –Changes to Marketed New Drugs • attempted to entrench Changes to Marketed New Drug Products policy in the Food and Drug Regulations • proposed in Canada Gazette 1 (March 1997) • withdrawn in October 1998 (due to perceived inflexibility of Regulations to adapt to “rapidly changing regulatory environment”)

19. Changes in Product-Specific Facility Information • Changes in Product-Specific Facility Information (revised in 2004) • Provides guidance to the biological drug industry on making changes to a facility in which an approved drug product is being fabricated • Based upon experience gained by BGTD, the guidance was revised in 2004 • Industry request for more examples

20. Proposal to address these Issues • Development of a new, more comprehensive guidance document that: • is more consistent with modern principles of risk management • improves international harmonization • replaces out-dated policies and guidances • is better supported by the Food and Drug Regulations • increases the transparency and consistency of the review process • incorporates “design space” concept of ICH Q8

21. Key Elements of Proposal • Revised criteria by which to categorize changes to drugs or drug products • Provision of more comprehensive guidance as to information required in support of change

22. Key Elements of Proposal • Revised criteria result in two main types of change: • those that require prior review and approval by Health Canada • those that may be implemented without prior review and approval by Health Canada

23. Key Elements of Proposal • Changes that require prior review and approval by Health Canada • Current SNDs, and many NCs (particularly proposed changes to the conditions of use, adverse event information, implied claims, or patient information) • Changes that may be implemented without prior review and approval by Health Canada • Current Level 3 and 4 changes, and some current NCs

24. Overview of New Guidance • Drafting of new Post-NOC Changes guidance has begun • Structure of new guidance: • modelled after EU Variations Guidance format with “Conditions” and “Supporting Documentation” for each change example

25. Overview of New Guidance • Structure of new guidance: • Safety & Efficacy (Labelling) follows format of Product Monograph • Quality follows ICH CTD progression

26. Overview of New Guidance • Content of new guidance: • greater detail • additional criteria to distinguish between levels of change • supporting documentation recommendations • greater number of change examples

27. Sample Guidance Page (Safety and Efficacy) Supplement (Type I): Any change that has the potential to increase the risk associated with the use of a drug by the Canadian population. This includes but may not be limited to the following: • The addition of any claims, explicit or implicit and/or changes to the current claim, that has the potential to increase exposure levels of the current patient population and/or introduce a new patient population to the drug. • The deletion of, or weakening of, any recommendations or data regarding the management of the current patient population. c) The addition of data, other than that related to adverse reactions, which does not result in any other changes to the information provided to the Health Care Professional or consumer.

28. Sample Guidance Page (Safety and Efficacy) Supplement (Type II) or Notifiable Change: Any change that has the potential to improve the management of risk to the Canadian population presently indicated for use of the drug. This includes but may not be limited to: • The identification of patient subgroups, or conditions of use for which the benefit to risk ratio of the drug has the potential to be less favourable than that of the current patient population. • The addition of , or strengthening of, any recommendations or data regarding the management of the current population. c) The addition of any data related to adverse reactions.

29. Sample Guidance Page (Quality)

30. Implementation Option 1 • Option 1: Align with Existing Regulations • Supplements (prior review and approval) and • Annual Notifications (no prior review and approval)

31. Implementation Option 1 Where would the Notifiable Changes go? • some changes would become Supplements and others would become Annual Notifications

32. Implementation Option 1 • Supplements • Type I: Would include all current Supplements, retaining review target time • Type II: Would include many current NC type changes. Retention of current NC review target time, but elimination of the default

33. Implementation Option 1 • Annual Notifications: • to include some current Level 2 (NC) as well as level 3 and 4 changes • may be implemented by the sponsor provided recommended conditions have been met and supporting documentation is available • update of all changes submitted annually • subject to periodic auditing

34. Implementation Option 2 • Option 2: Phased Approach linked to New Regulatory Framework • Phase 1: • Publish new guidance that includes revised classification criteria and recommended supporting documentation for different levels of change • retain “Notifiable Change”, but reflects definition of Type II Supplements, as defined by new Guidance • Phase 2: • all levels of change to be incorporated in the modernized regulatory framework as part of the Progressive Licensing Project

35. Option 1 vs 2 ? • Considerations in the assessment of Options 1 and 2: • Workload implications • Impact of PM(NOC)Regulations • Efficiency gains • Cost recovery implications • Progressive Licensing initiative to modernize Regulatory framework

36. Next Steps • Feedback provided from CAPRA members to be considered during preparation of draft guidance • Draft guidance to be posted on Health Canada website • Consider stakeholder feedback in finalization of guidance

37. Thank You Contact Information: Post-NOC Changes Project lead: Randy Duhaime Senior Policy Analyst Bureau of Policy, Science and International Programs, TPD (613) 948-8414 randy_duhaime@hc-sc.gc.ca

38. Moderated Panel-Questions • 1. What are the most common “gray areas” that should be addressed in a new guidance with respect to: • A. Safety & Efficacy (Labelling) • B. Quality (Chemistry & Manufacturing) • C. Miscellaneous (process, administrative changes, etc)?

39. Moderated Panel-Questions • 2. What modifications to Health Canada’s current system of managing post-NOC changes would facilitate the concurrent filing of changes internationally?

40. Moderated Panel-Questions • 3. There are often times when the level of change is unclear. • A. Is the current system for verifying the level of change efficient and effective? • B. What can sponsors and/or Health Canada do to improve the process?