NCMD Medical Device Forum May 16, 2005

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NCMD Medical Device ForumMay 16, 2005

• Combination Products FDA Regulatory Update
• Patricia Y. Love, MD, MBA
• Associate Director
• Office of Combination Products

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What Are Combination Products?

• Combinations of differently regulated products
• Drug-device
• Device-biologic
• Drug-biologic
• Drug-device-biologic

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Combination Products Vary

• They can be
• Physically or chemically combined into one
  entity 21 CFR 3.2(e)(1)
• Co-packaged 21 CFR 3.2 (e)(2)
• Separately provided cross-labeled products 21
  CFR 3.2(e)(3)

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Office of Combination Products

• Assignment of combination products
• Ensure timely and effective premarket review
• Consistent and appropriate postmarket regulation
• Dispute resolution (timeliness vs. substance)
• Review/update guidance, agreements, practices
• Report to Congress
• Resource to sponsors and review staff

P. L. 107-250 enacted 10-26-02 office
established 12-24-02
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Critical Regulatory Challenge

• Making combination product regulation
• Appropriate
• Consistent
• Clear
• Predictable

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Topics Activities Approaches

• Classification Assignment
• Internal process Dispute resolution
• User Fee
• GMP
• Other Activities
• Number of Marketing applications
• Safety reporting
• Mutually conforming labeling
• Next steps

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• Classification and Assignment

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Classification and Assignment

• Office of Combination Products
• Determines the product classification
• Drug, device, biological product, or combination
• Determines the primary mode of action
• Identifies lead center
• Identifies premarket regulatory pathway
• Provides preliminary information on postmarket
  authorities

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Assignment Determination Process

• Formal
• or
• Informal

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Formal Assignment

• Request for designation (RFD), 21 CFR 3.7
• complex issues
• binding decisions
• 60-day clock sometimes
  tight

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OCP Formal Classification Assignments
10/1/03 9/30/04
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• Challenge
• What is PMOA?
• No definition

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PMOA Proposed Rule May 7, 2004 Federal Register

• Defined PMOA
• Set forth criteria for determining the PMOA in
  the face of uncertainty
• Provided an assignment algorithm

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PMOA Proposed Rule May 7, 2004 Federal
Register, contd

• Mode of Action the means by which a product
  achieves a therapeutic effect
• Therapeutic any effect / action intended to
  diagnose, cure, mitigate, treat, or prevent
  disease, or affect the structure or any function
  of the body
• Three modes of action device, drug, biological
  product,
• Combination products ? usually more than one mode
  of action

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PMOA Proposed Rule May 7, 2004 Federal
Register, contd

• Primary Mode of Action
• The single mode of action of a combination
  product that provides the most important
  therapeutic action of the combination product.

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PMOA Three Hypothetical Examples

• Vision-correcting contact lens with drug to make
  lens more comfortable
• Contact lens as drug delivery system
• Vision-correcting contact lens with concurrent
  delivery of glaucoma drug
• (Example in the proposed rule)

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PMOA Proposed Rule May 7, 2004 Federal
Register, contd

• Algorithm
• PMOA determinable ? assign there stop
• Most important therapeutic action uncertain ?
• Is there an agency component with CPs that raise
  similar SE questions for CP as a whole?
• Yes, then ? assign there stop
• No, then
• Which agency component has the most expertise
  related to the most significant SE questions for
  the CP? ? Assign there stop

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PMOA Proposed Rule May 7, 2004 Federal
Register contd

• Comment period closed August 2004
• Docket comments were generally favorable
• Requested clarifications (precedents, intended
  use, intercenter agreements,regulatory/ statutory
  implications, marketing applications)
• More examples
• Status expect final publication soon

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Challenges Assignment

• RFDs are voluntary . . . we dont see all
  products for assignment . . . Industry / staff
  preferences may not fit with what the law allows
• Informal assignments For many products
• Phone / other meetings (pre-IND/IDE)
• Transparency often is challenging, but
• Jurisdictional updates and 140 published
  determinations (OCP website)

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• Once assigned, then what?

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Different Regulatory Environments
CDER
CBER
CDRH
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Once assigned, then what contd?

• Dont have specific regulatory schemes for
  combination products per se . . .
• Currently work within existing statutory
  framework
• While considering what needs new regulations

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• Premarket review

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Premarket Review

• Statute OCP to ensure timely and effective
  premarket review by overseeing timeliness and by
  coordinating reviews involving more than one
  agency Center

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Review Process

• SOP for intercenter consultation process
• Consults count same priority as assigned
  products
• Team agreement on timing
• http//www.fda.gov/oc/combination/consultative.htm
  l
• Active monitoring/facilitation web-enabled
  database (gt 200 in FY 04)
• Tracking and Reporting of Other Combinations
• Check classifications of premarket submissions

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Combination Products Process Evolution

• Establish and clarify regulatory pathways
• Reviewer tools and training
• Establish and facilitate intercenter working
  groups and internal MOUs
• Available informally and formally to both
  sponsors and review staff
• Facilitate meetings, consider broad class or
  specific CP concerns, etc.

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What if you disagree or there is a glitch in
the process?

• We work to resolve disputes by
• Informal and formal meetings
• Phone Calls
• Email
• Dispute Resolution Guidance

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Combination Product Dispute Resolution Guidance,
Final 2005

• Combination Products Timeliness of Premarket
  Reviews Dispute Resolution Guidance
• www.fda.gov/oc/combination/dispute.pdf
• Consideration of PDUFA / MDUFMA / other
  performance goals
• Procedural/process for sending formal disputes to
  OCP

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• Postmarket regulation

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Postmarket regulatory challenges

• Statute OCP to ensure consistent and appropriate
  postmarket regulation
• Good manufacturing practice
• Number of marketing applications
• Safety reporting requirements

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Manufacturing Control Challenges

• Manufacturing control regulations are associated
  with a range of practices, procedures, policies.
• QS regulations PMA, HDE, 510(k)
• CGMP regulations NDA
• Biologic product regulations BLA

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Good Manufacturing Practice Guidance Draft
September 29, 2004

• CGMP and QS similar but tailored to the product
  for which they were designed.
• Compliance with the regulations for the
  constituent
• Each constituent part is subject to its governing
  GMP regulations before combination.
• During and after combination (21 CFR 3.2(e)(1) or
  (e)(2)), both regulations apply.
• Compliance with both regulations can generally be
  achieved using either (e.g., by using the system
  in place at a facility) Parallel systems not
  needed.

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Good Manufacturing Practice Guidance Draft,
Contd

• Draft guidance lists key provisions to consider
  in ensuring compliance with both regulations
• Other provisions may be appropriate to consider,
  depending on the combination product

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Under Part 820 Operating Manufacturing Control
System Key Provisions to Consider
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Under Part 210/211 Operating Manufacturing
Control System Key Provisions to Consider
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Good Manufacturing Practice Guidance Draft,
Contd

• Communication is critical
• Early discussion of manufacturers implementation
  proposals as soon as possible (e.g., pre-IND/IDE)
• Consider the risks of the combination product,
  its technology, and anticipated post approval
  changes

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Good Manufacturing Practice Guidance Draft,
Contd

• Communication would include
• Manufacturers of constituent parts
• FDA intercenter team
• Product reviewers
• GMP/QS experts
• Field inspectors
• OCP

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Good Manufacturing Practice Guidance Draft,
Contd

• Status comment period closed December 3, 2004
• http//www.fda.gov/oc/combination/default.htm
• Docket comments
• Generally favorable
• Requested clarification of terminology, technical
  differences, examples, etc.
• Inspections guidance information, FDA training of
  inspectors

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• Marketing Applications
• for
• Combination Products

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Combination Product Marketing Applications

• Number and type of marketing applications
• User fee implications

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Application User Fee Guidance Final April 2005

• Single marketing application fee associated with
  that type of application waivers / reductions
  under PDUFA/MDUFMA
• For innovative combination products with two
  applications PDUFA barrier to innovation waiver.
• When FDA requires 2 applications, we expect to
  reduce the fee regardless of financial status
• When sponsor submits 2 applications, the barrier
  to combination product innovation will be
  considered
• MDUFMA and PDUFA applications reduce PDUFA fee
  by amount of MDUFMA fee
• Two PDUFA applications reduce each PDUFA fee by
  half
• http//www.fda.gov/oc/combination/default.htm

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Combination Product Users Fees, contd

• Eligibility factors considered for innovative
  combination product waiver
• CP as a whole is innovative (e.g., unmet medical
  need, one constituent is NME, priority/fast-track/
  expedited review status)
• Applications only for CP use together
• FDA requiring 2 marketing applications
• Doesnt meet small business waiver

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Number of Marketing Applications

• Developing guidance anticipates the following
• One application will be sufficient for most
  combination products e.g.,
• Chemically, physically, or otherwise combined
  into a single entity and most co-packages
• Two applications may be
• Required by FDA in some circumstances
• Requested by industry in some circumstances
• Nearing completion for publication and public
  comment

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• Other ongoing activities

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Ongoing activitySafety Reporting - Postmarket

• Several regulatory requirements to reconcile
• 314.80, Adverse Drug Experience (ADE)
• 600.80, Biological product adverse experience
• 606.170, Blood component adverse experience
• 600.81, Vaccine adverse events (VAERS)
• 803, Medical Device Reporting (MDR)
• IT and database issues to resolve
• Draft nearing completion for public comment

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Ongoing activity Mutually Conforming Labeling

• DIA-FDA Workshop, May 10th
• Focused hypothetical company A drug marketed,
  company B device for use with A
• Public health legal implications of requiring
  vs. not requiring mutually conforming labeling
• FR notice and slides available at
  http//www.fda.gov/oc/combination/

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More to do?

• Publish and finalize guidance/regulations in
  process
• Other priorities include
• Post-approval changes
• Submission format content
• Chemical action
• Ongoing evaluation of impact on existing
  policies/practices
• Continued public stakeholder input at meetings

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Recommendations

• Pathway evolution clarifications one size
  doesnt fit all CPs
• Focus on the additive/modifying effect of the new
  constituent
• Consider GMPs, postmarket issues, labeling,
  expected changes throughout development
• Early discussions with both centers and all
  critical manufacturers at the table

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To Contact Us

• Office of Combination Products
• 15800 Crabbs Branch Way (HFG-3)
• Rockville, MD 20855
• [phone]
• combination_at_fda.gov
• http//www.fda.gov/oc/combination/