1. Industry Perspective on Challenges for Product Developers - Drugs Christine Allison, M.S., RAC Associate Regulatory Consultant, Global Regulatory Affairs (CM&C) Eli Lilly and Company Regulatory Challenges for Drug/Device Combination

2. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 2 Presentation Goals Introduction Regulatory challenges during development Regulatory challenges during market application Regulatory challenges post approval Challenges working with partners Global challenges Summary Conclusion

3. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 3 Introduction Lilly experience on Drug/Device combination products - Pulmonary inhalation system for systemic delivery of drug (development experience) - Pen injectors (both development and post approval experience)

4. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 4 Regulatory Challenges during Development Where do we go for regulatory consultation prior to lead Center designation? For drugs For devices Lilly comments Support the concept of single focal point Recommend that the Office of Combination Products be the coordinator and facilitator for identifying the appropriate Center(s) for technical consultation prior to lead Center designation

5. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 5 Regulatory Challenges during Development Consistency in Lead Center designation Sometimes sponsors choose to go to the individual Center instead of Office of Combination Products Lead Center assignment may be influenced by sponsors first contact with the Agency Often consulting Center(s) are not defined at the time of lead Center assignment Lilly comments Suggest that internal procedure be developed to guide each Center for routing those requests to the Office of Combination Products for review to ensure the consistency of lead Center designation Recommend that Office of Combination Products also identify the consulting Center(s) at the time of lead Center assignment

6. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 6 Regulatory Challenges during Development Major CMC challenges for innovative drug delivery system Commercial system (formulation and device) required for pivotal studies - Technical challenges - Early resource commitment prior to phase 2/3 Establishment of comparability between pre-commercial and commercial systems Lilly comments Clear and documented expectations from the Agency are needed Frequent dialogue with the Agency regarding specific issues is critical throughout the development process Consider the role of bridging strategies to allow product/process improvements during development through commercialization

7. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 7 Regulatory Challenges during Development Major CMC challenges for innovative drug delivery system Drug/Device integrated system - Formulation challenges - Device challenges - System challenges Requires frequent consultation with multiple FDA Centers/Divisions Lilly comments Alignment and communication with multi Centers/Divisions has been challenging Agency’s review team should include members from all relevant Centers and Divisions from the first sponsor meeting

8. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 8 Regulatory Challenges during Development Quality System Which regulations should apply for the drug/device combination? Drug cGMP (21 CFR § 210) or Device QSR (21 CFR § 820) or both? Which compliance guidance will be used during pre-approval inspection? Lilly comments Recommend that the drug production process conforms to the drug regulations and the device production process conforms to the device regulations Clear policy is needed with regard to FDA expectations for pre- approval inspections of combination products Encourage investigators be trained to perform combination product inspections using the appropriate regulations for each component of the combination

9. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 9 Regulatory Challenges during Development Regulatory Reporting The requirements are unclear for AE and device reporting during a clinical study of a drug/device combination Should we follow 21 CFR § 312 or 21 CFR § 812? Issue for IND drug delivery systems: - Adverse device effects - Inclusion of device investigation results Lilly comments Reporting requirements for both drugs and devices should be applied as appropriate These reports should be directed to the same Center(s) that led the review

10. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 10 Regulatory Challenges during Market Application Market Applications Single or Dual submissions? Dual user fees? Format – Where to include device information in the CTD for a combination where CDER is the lead Center? What kind of device information needs to be included in a drug submission? Lilly comments Support the concept of a single premarket review mechanism leading to a single approval of combination products understanding that there will be exceptions when a dual submission is more appropriate Recommend standardization of submission format and data requirements for device information to be included in a CTD submission. Phase appropriate data requirements for devices to be included in the INDs.

11. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 11 Regulatory Challenges Post Approval Manufacturing changes, device changes, and device labeling changes No clear guidance on how to handle changes on the device portion of a drug/device combination that is submitted to FDA in a drug market application Lilly comments: Recommend the use of CDRH 510(k) decision tree as a guideline for device changes If 510(k) not required in the decision tree– annual report [21 CFR§314.70(d)] If 510(k) is required in the decision tree – NDA supplement [21 CFR§314.70(b)or(c)]

12. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 12 Regulatory Challenges Post Approval Regulatory Reporting Clear guidance is needed on the requirements for the adverse event and device reporting for a drug/device combination product Which regulation applies? 21 CFR § 314 or 21 CFR § 803? Issue for NDA drug delivery systems: - Reportable malfunctions - Inclusion of device investigation results Lilly comments Reporting requirements for both drugs and devices should be applied as appropriate These reports should be directed to the same Center(s) that led the review and cleared the product

13. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 13 Regulatory Challenges Post Approval Cross labeling of products intended to be used together Currently the drug submission regulations do not include what changes need to be made to the drug labeling in order to reach conforming labeling No user fee associated with these label change submissions, therefore no set review times In some cases, it could take years to add a cleared device to the drug label Repeated review of data sets that have already been reviewed by the other center Requested additional data beyond what was required by the other Center Lilly comments Clear guidance is needed on how to obtain mutually conforming labeling Suggest allowing the cleared device to be included in the drug labeling as appropriate and the communication of that labeling change be made in the Annual Report [21 CFR §314.70(d)]

14. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 14 Challenges Working with Partners Often a device company may work with multiple drug companies with the same device platform Dealing with confidentiality Sometimes difference in regulatory strategic approach

15. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 15 Global Challenges A drug/device combination approved under CDER with an NDA may require a Market Authorization for the drug and a CE Mark for the device in EU. Submission document Quality system requirements Post approval change Regulatory reporting Labeling Compliance inspection

16. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 16 Summary Challenges throughout the entire product life cycle for innovative drug/device products Guidance is needed in many areas such as quality system requirements, post approval changes, reporting, and cross labeling Continued dialogue between Sponsors and the Agency is critical to ensure successful development and timely review of market applications

17. July 8, 2003 FDA WorkshopCopyright © 2003 Eli Lilly and Company 17 Conclusion When setting policies and guidance, consider: Single focal point (Office of Combination Products) Keep it simple Reduce redundancy Not only market applications but also post approval requirements Global harmonization needs