AdvaMed Combination Products Seminar Case Studies and Practical Challenges Cross-Labeled Products May 29, 2008

1. AdvaMed Combination Products SeminarCase Studies and Practical ChallengesCross-Labeled ProductsMay 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

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

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 email • 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 email • 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

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

17. 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 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 Difference in Data Requirements from FDA Centers

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

19. Data Requirements - Animal • 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

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. 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 Navigating the Different FDA CentersCultural Differences

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

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 - 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

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