# Presentation: 155950

## 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**

## Presentation Goals

- Introduction
- Regulatory challenges during development
- Regulatory challenges during market application
- Regulatory challenges post approval
- Challenges working with partners
- Global challenges
- Summary
- Conclusion

## 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)

## 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
*	*

## 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
*	*

## 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*	*

## 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
*	*

## 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

## 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

## 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.

## 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)]

## 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

## 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)]

## 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

## 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

## 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

## 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