1. 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

2. Outline
Introduction – Definitions, General Challenges and Considerations
Development Arrangements for Cross-Labeled Products - Different Case Scenarios
Collaboration Between Device and Drug Companies – Examples:
Joint Venture
Joint Development
General Agreement
Going it Alone - Single device company
No Collaboration (One Company Developing Both Products)
No Collaboration using commercially available drug/biologics

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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
Development of joint regulatory strategy for the combination product – targeted indications and claims; interactions with regulatory agencies; impact of potentially broader indications for the device component on registration plans

9. 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

10. 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

11. 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

12. Regulatory Considerations Commercial Phase
Establish post-marketing issues in agreement
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
Agreements on -
Branding
Marketing/distribution logistics
Product Changes/Change Controls
Regulatory Filings – difference in regulatory requirements – prior approvals vs. notifications (may need OCP intervention)
AE Reporting

13. Pre-Market Reporting Considerations
Establish a written agreement on how to share safety information
Case Report Forms in Clinical Studies need to capture device-related 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
Responsibility for follow-up if required
Annual reports for IDE, IND
Designated Contact person

14. 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
Responsibility for follow-up if required
Literature reviews
Periodic Audits
Periodic Reports
Contacts for each company

15. 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
Involve regulatory in contract negotiation
Regulatory representation in steering committee and development team
Open and transparent communication – one objective

16. 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
Experienced regulatory professionals for both partners – ideally on combo product or both product development
Cross training for awareness of different regulatory schemes, requirements and cultures
Clear understanding of priorities and approach to regulatory risk approach
Partnership Success:
Always establish a win-win relationship not a win-loose
Define roles and responsibilities but be prepared for step up when necessary to meet critical deadlines
Understand what motivates each company-
Be prepared for change
Project Oversight
Joint Clinical/Regulatory/ Dev/IT Council: oversee day-to-day activities, set plans, establish procedures, charter for decision making and escalation
Large vs. small company differences
Regular communication plan and rules of engagement
Establish common project plans with sufficient detail to establish agreed upon deadlines
Insure that top management is apprised on a regular basis and establish “buy in”
Communication is key to success: within the team, within each organization, to the organization’s management and between the companies
Formal joint development team and senior management oversight committee for dispute resolution
Business/Marketing/Legal Council: Establish business expectations; Review opportunity for changing marketplace/factors; launch/marketing plans
Business Dev/Clinical/Marketing/Reg Sr. Management team: Go/No Go decisions; oversight of timelines and progress
Executive Council: One member of each companies top level management to make decisions when teams are at impass
Primary contact – core team member
Management – routine updates/escalation procedure/criteria – discuss strategic issues
Establish a cross-functional project team for each company with members from appropriate disciplines
Designated project plan “owner” and routine updates and communication with team
Establish open communication channel with FDA (OCP, CDRH, CBER and CDER) as soon as possible and strive for Pre-IND (or IDE meetings) to educate them on the combination product and gain feedback on the clinical and regulatory strategy.
Who can attend FDA meetings
Have routine team meetings with set agenda; include face-to-face meetings on periodic basis
Milestones with defined Go/No Go criteria
Clear roles and responsibilities
Access to data as much as possible
Attendance at FDA meetings
Early agreement and development on draft labeling and claims
Post market activities clearly delineated

17. Difference in Data Requirements from FDA Centers
CDER/CBER
Detailed Requirements via Guidances
ICH FDA Guidance
Details of Manufacturing Information (CMC)
Validation Data
Clinical Data
Randomized Controlled Trials
Phase IV Commitments
Risk Management Plans
Labeling (PI) Format and Content
Trade Name Review/Medication Error Prevention
ADR
Post Approval Changes/Notifications
CDRH
Bench Testing
Preclinical (animal) Testing
Biocompatibility Standards
OC Review of Manufacturing Data
OSB Involvement of CoA Studies
Risk Management – ISO Standard
Human Factors Testing
MDR Reporting
Post Approval Changes – Prior Approvals

18. 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
Formulation development
Device design input/verification/validation
Specification Setting
Design Intent vs. Regulatory Specifications
Established by the individual manufacturer
Established based on the constitutive part and FDA guidance
Established based on stage of product development
Biocompatibility testing shared responsibility for the partners
ICH vs. ISO/AAMI Standards vs. FDA Guidances
Drug/Device Interface & Compatibility Testing
Release vs. Shelf Life (drug/device compatibility and stability – degradation products)
Analytical method validations
Compatibility – Impact of biologic on device
Stability – Impact of device on biologic
The bottom line is understanding how each constituent impacts the other as part of the system
Pilot/Scale Ups
Manufacturing runs
Process Validation
3 consecutive batches
cGMP/QS Considerations

19. Data Requirements - Animal
ISO 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
Make sure that the terminology is clearly understood and partners have good understanding of each other requirements
ISO Biocompatibility vs. ICH Safety
Chronic Testing
Carcinogenicity
Drug/device interface interaction/ degradation product testing
Appropriate Animal models

20. Data Requirements - Clinical
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

21. 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

22. Possible Drug Regulatory Paths
Drug information could be submitted as:
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)

23. 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/ s and faxes
Project Manager (CSO) as point person
IND Amendments require no formal “approval”
IND Hold
Review Clock

24. 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

25. Project and Strategy Considerations
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

26. 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

27. 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
Only talk about drugs – because biologics is such a difficult arena

28. Project and Strategy Considerations
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

29. 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

30. 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 (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

31. 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

32. Spinal Cord Injury

33. Stroke