PostNotice Of Compliance Changes

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

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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

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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

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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

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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)

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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

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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

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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
  suppliedis 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

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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)

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Focus on Major Players
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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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Overview of New Guidance

• Structure of new guidance
• Safety Efficacy (Labelling) follows format of
  Product Monograph
• Quality follows ICH CTD progression

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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

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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.

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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.

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Sample Guidance Page (Quality)
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Implementation Option 1

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

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Implementation Option 1

• Where would the Notifiable Changes go?
• some changes would become Supplements and others
  would become Annual Notifications

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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

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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

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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

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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

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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

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Thank You

• Contact Information
• Post-NOC Changes Project lead
• Randy Duhaime
• Senior Policy Analyst
• Bureau of Policy, Science and International
  Programs, TPD
• [phone]
• randy_duhaime_at_hc-sc.gc.ca

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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)?

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Moderated Panel-Questions

• 2. What modifications to Health Canadas current
  system of managing post-NOC changes would
  facilitate the concurrent filing of changes
  internationally?

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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?