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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 Make sure that the terminology is clearly understood and partners have good understanding of each other requirements ISO 10993 Biocompatibility vs. ICH Safety Chronic Testing Carcinogenicity Drug/device interface interaction/ degradation product testing Appropriate Animal models

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

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

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)

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

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

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

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

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

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

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

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

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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