industry perspective on challenges for product developers - drugs christine allison, m.s., rac...

Industry Perspective on Challenges for Product Developers - Drugs

Christine Allison, M.S., RACAssociate Regulatory Consultant, Global Regulatory Affairs (CM&C)

Eli Lilly and Company

Regulatory Challenges for Drug/Device Combination

July 8, 2003FDA Workshop

Copyright © 2003 Eli Lilly and Company

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Presentation Goals

• Introduction

• Regulatory challenges during development

• Regulatory challenges during market application

• Regulatory challenges post approval

• Challenges working with partners

• Global challenges

• Summary

• Conclusion



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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)



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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



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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



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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



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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



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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



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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



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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.



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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)]



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Regulatory Challenges Post ApprovalRegulatory 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



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Regulatory Challenges Post ApprovalCross 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)]



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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



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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



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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



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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

industry perspective on challenges for product developers - drugs christine allison, m.s., rac...

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