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AdvaMed Combination Products
Seminar
Case Studies and Practical Challenges
Cross-Labeled Products
May 29, 2008
Winifred C. Wu
V.P. Regulatory Affairs
Medtronic Neuromodulation
Diana Salditt
Distinguished Regulatory Affairs Advisor
Medtronic Corporate Regulatory Affairs
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Outline
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Introduction – Definitions, General Challenges and
Considerations
Development Arrangements for Cross-Labeled
Products - Different Case Scenarios
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Collaboration Between Device and Drug Companies –
Examples:
1. Joint Venture
2. Joint Development
3. General Agreement
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Going it Alone - Single device company
1. No Collaboration (One Company Developing Both Products)
2. No Collaboration using commercially available drug/biologics
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Definitions
What is a cross-labeled combination product?
21CFR 3.2(e)(3)&(4)
• Product provided separately and intended for use only
with an individually specified product where both are
required to achieve the intended effect and labeling
changes are required upon approval
• Investigational product provided separately and
proposed for use only with an individually specified
product where both are required to achieve the
intended effect
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Definitions
Examples of Cross-Labeled Products:
• Intrathecal drug therapies
• Therapy requiring site specific delivery using specialized
delivery systems
• Photosensitizing drug and activating laser/light source
• Iontophoretic drug delivery path and controller
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General Considerations and Challenges
• Factors that increase the likelihood that two products
packaged and sold separately are a combination product
include: known compatibility or stability issues with
similar products; designed with unique characteristics
and validated for use together (e.g. ability to access a
difficult target; unique delivery characteristics)
• Need for cross-labeling may determine the need for
collaboration between companies
• Fewer regulatory approval options with biologics – no
biosimilar provisions in the US yet; not eligible for
505(b)(2) process
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General Considerations and Challenges
• US regulation defines cross-labeled products as
combination products but in the EU, Canada, Australia
and Japan, these products are regulated separately as
devices or drugs/biologics
• The particular drug/biologic may not be available in
these regions but yet the device is approved (e.g. via CE
Mark, etc.)
• The sponsor for the drug/biologic may be another
company without a business agreement with the device
manufacturer
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Case 1
• Company A and Company B agree to collaborate to
develop combination products
• Establish a Joint Venture that is funded and managed by
both companies
• Joint Development Team
• Complete transparency
• One or two regulatory applications
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Project and Strategy Considerations
• Development of joint regulatory strategy for the
combination product
• Balancing expectations of joint venture and individual
corporations – priorities and internal policies/procedures
• Quality system structure
• Interaction between companies regarding change
control, adverse event reporting, advertising and
promotion review
• Functional alignment
• Regulatory agency interactions simplified
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Case 2
• Company A and Company B decide to collaborate in
development of a cross-labeled therapy
• Business Agreement In Place – U.S. and/or OUS
• Company A responsible for development and approvals
for device components
• Company B responsible for development and approvals
for drug/biologic components
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Project and Strategy Considerations
• Development of joint regulatory strategy – alignment on
targeted labeling/claims
• Level of access to information on partner’s product
• Plan for communication with regulatory agencies and
exchange of information with partner
• Coordination of post-market activities such as change
control, adverse event reporting, labeling revisions,
advertising and promotion review
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Regulatory Strategy
• RFD (Request for Designation) from Office of
Combination Products – Optional
• IND or IDE (depends on PMOA) sponsored by Company
A or B
• Define/clarify review responsibilities of different Center
reviewers
• Utilize Master File System (Drug Master File (DMF) or
Device Master File (MAF) for proprietary information
• Understand Type of Reviews - Collaborative or
Consultative
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Regulatory Considerations
Commercial Phase
• Establish post-marketing issues in agreement
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Branding
Launch Activities
Marketing/distribution logistics
Advertising/promotional coordination
Post approval study requirements/risk management
strategies
Product changes/change controls
Regulatory filings
AE reporting
Post Market Safety Periodic Reports
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Pre-Market Reporting Considerations
• Establish a written agreement on how to share safety information
• Case Report Forms in Clinical Studies need to capture devicerelated and drug-related events
• Evaluate need for data monitoring safety board
• Expert Physician Panel
• Best if both Sponsors agree and collaborate on membership
• Information to be shared
• Format and potential IT issues
• Timing of sharing of information relevant to device/drug relations
• Method (patient confidentiality must be maintained)
• Fax, Letter, secure email
• Responsibility for follow-up if required
• Annual reports for IDE, IND
• Designated Contact person
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Post-Market Reporting Considerations
• Establish a written agreement on how to share safety
information
• Responsibility for reporting AEs of each product
• Geographical responsibility (US, OUS)
• Information to be shared
• Format and potential IT issues
• Timing of sharing of information
• Method of Communications – e.g. Fax, Letter, secured email
• Responsibility for follow-up if required
• Literature reviews
• Periodic Audits
• Periodic Reports
• Contacts for each company
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Joint Partnership Best Practices
• Involve regulatory in contract negotiation and due diligence
• Regulatory representation in steering committee and development
team
• Delineation of roles and responsibilities – e.g. CRO, etc.
• Issue escalation/resolution and termination criteria
• Clearly defined governance structure and decision making process
(including issue escalation/resolution and termination process)
• Open and transparent communication – one common goal
• Clear definition of milestone/commitments
• Sub-agreements for development and post approval details, e.g.
– Development and supply agreement
– Quality Agreement
– Co-marketing Agreement
– Post Approval Collaboration Agreement
– Safety Exchange Agreement
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Regulatory Coordination Between Partners
– Best Practices
• Experienced regulatory professionals for both partners – ideally on
combo product or development of both product types
• Cross training for awareness of different regulatory schemes,
requirements and cultures
• Clear understanding of priorities and regulatory philosophy/stance
(e.g. regulatory risk tolerance; timing and nature of
communication/collaboration with regulatory agencies)
• Formal joint development team and senior management oversight
committee for dispute resolution
• Clear roles and responsibilities
• Access to each others’ data as much as possible
• Attendance at FDA meetings
• Early agreement and development on draft labeling and claims
• Post market activities clearly delineated
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Difference in Data Requirements from FDA
Centers
CDRH
• Bench Testing
• Preclinical (animal) Testing
– Biocompatibility Standards
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OC Review of Manufacturing Data
OSB Involvement of CoA Studies
Risk Management – ISO Standard
Human Factors Testing
MDR Reporting
Post Approval Changes – Prior
Approvals
CDER/CBER
• Detailed Requirements via
Guidances
– ICH FDA Guidance
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Details of Manufacturing
Information (CMC)
Validation Data
Clinical Data
– Randomized Controlled Trials
– Phase IV Commitments
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Risk Management Plans
Labeling (PI) Format and Content
Trade Name Review/Medication
Error Prevention
ADR
Post Approval
Changes/Notifications
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Difference in Data Requirements
Between FDA Centers
• Formulation development
• Device design input/verification/validation
• Specification Setting
– Design Intent vs. Regulatory Specifications
• ICH vs. ISO/AAMI Standards vs. FDA Guidances
• Drug/Device Interface & Compatibility Testing
– Release vs. Shelf Life
– Analytical Methods/validation
– Stability
• Pilot/Scale Ups
• Process Validation
• cGMP/QS Considerations
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Data Requirements - Animal
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ISO 10993 Biocompatibility vs. ICH Guidance
Chronic Testing
Carcinogenicity
In vivo Drug/device interface interaction/ degradation
product testing
• Distribution studies for the combo therapy
• Appropriate animal models for the combo therapy
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Data Requirements - Clinical
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Level of clinical evidence
– Different standards for clinical evidence – valid scientific evidence for
PMA devices vs. substantial evidence for drugs/biologics
– Number of studies
– Type of studies
– Safety data base
– Local vs. systemic adverse events
– Leveraging of historical data
– Study Conduct
Documentation of Clinical Data
– Data cut-off
– Clinical reports – level of details
– Statistical data – raw data
GCP Compliance
• ICH vs. IDE
• Inspections
• Clinical Investigator Misconduct
Post Submission Updates
– E.g. 4-mo Safety Updates for NDA
Post approval Studies/Risk Management Plan
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Possible Device Regulatory Paths
Device information could be submitted as a/an:
– Right of Reference to Approved Device Approvals
(e.g. 510(k); PMA)
– As Part of (CMC) section of an IND/NDA
– Device Master File to support partner’s IND
– IDE (not desired)
– new 510(k)
– PMA
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Possible Drug Regulatory Paths
Drug information could be submitted as:
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Part of an IDE, PMA, or 510(k)
IND
NDA
sNDA (already approved for indication - e.g. new
route and/or new indication)
• NDA (cross-reference) for supportive data (i.e. pre-clinical,
PKDM, general clinical safety)
– Drug Master File (DMF)
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Navigating the Different FDA Centers
Cultural Differences
• CDRH
– More Informal
Communications
• Interactive Review
Guidance
– Lead reviewer interfaces
with Sponsor
– IDE Supplement Requires
Approval
– “Conditionally” approved
common for IDE/IDE
Supplement
– MDUFDA Goals
• CDER/CBER
– More Formal and
Established
Communication Protocol
• Meeting
• Phone/ E-mails and faxes
– Project Manager (CSO) as
point person
– IND Amendments require
no formal “approval”
– IND Hold
– Review Clock
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Case 3
• Company B (drug) has general agreement to develop a
drug suitable for several different devices (with similar
characteristics) from different manufacturers
• Periodic, informal and unstructured communications
• Device companies May get Right of Reference to
Submissions
• No information on content of (drug) submissions
• Approval for a constituent only when the other constituent
is approved
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Project and Strategy Considerations
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Somewhat common goal – make therapy available
Separate drug and device approvals
Separate sponsors
Communications occurs informally
No formal coordination post approval
Communications occurs when significant issues/crisis
occur
• Company contacts unknown
• Post approval changes including labeling not
consistently implemented
• Labeling maybe out of sync, lack of coordination in
managing potential safety issues
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Case 4
• Company A develops both the device and
pharmaceuticals
• Company A is the sponsor of regulatory approvals
• One or two applications
– NDA
– BLA
– PMA and NDA/BLA
• Packaged and Marketed Together
– U.S. and OUS
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Case 5
• No collaboration between drug and device manufacturer
• Device manufacturer responsible for all required data
• Maybe possible with off-patent drug(s) with established
performance standards (e.g. USP Monograph)
• Consideration of Request for Designation Highly
Recommended
• Post approval change control challenges
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Project and Strategy Considerations
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Regulatory schemes for each major region
Patent/exclusivity considerations
Other regulatory incentives – orphan drug/device
Potential for drug/device constituents to be developed for
other indications using different roles of administration
and/or dosage forms
• Compliance/Inspections/GMPs
• User Fees
• Distribution Logistics – State Regulations
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Project and Strategy Considerations –
No Partner
• Early consultation with OCP and Lead Center regarding
appropriate regulatory path and data requirements –
RFD?
• Leverage consultants (technical and regulatory) to fill
internal gaps
• Fully assess legality of leveraging other company’s data
• Formulate solid proposal for a system for tight change
controls – pre and post approval
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Project and Strategy Challenges –
No Partner
• No access to product expertise or drug product
information
• Rely on publicly available information – yet may not be
able to leverage in regulatory submission legally 505(b)(2) challenge
• Device sponsor provides all information to support
approval and includes all relevant information in labeling
• Need to establish robust system to evaluate impact of
product changes
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Closing Remarks for Regulatory
Professionals Engaging in Cross Labeled
Products
• Knowledge and understanding of both device and drug
regulations essential – “bilingual”
• Understanding of major differences in drug and device
development requirements, timelines and risks important
for project team and management
• Keen management and negotiation skills with multiple
parties
• Early collaboration with regulatory agencies is crucial for
success
• Expect longer development and “treacherous” path, often
blazing new trails
• Careful consideration of benefit vs. cost for business
case
• Not for the faint-hearted or non-adventurous
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Spinal Cord Injury
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Stroke
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