1. Best practices for study drug management and accountability throughout the study lifecycle in multi-site randomized controlled trials
Dikla Shmueli-Blumberg (presenter), Patricia Novo, Beth Jeffries, Lauren Yesko, Abigail G. Matthews, Julia Collins, Dagmar Salazar, Eve Jelstrom, Matthew Wright, Radhika Kondapaka
10 minute presentation, 5 minutes for questions

2. Drug Management
The process of handling study drug (Investigational Product, IP) following the protocol and GCP standards1 from the manufacturing phase or initial drug distribution through dispensing procedures at the research sites and through to final reconciliation and destruction.
IP responsibility (ICH E6(R2) GCP 4.6)
IP procedures (ICH E6(R2) GCP 6.4.7)
IP shipment documentation (ICH E6(R2) GCP )
Documentation of IP use at the site (ICH E6(R2) GCP )
IP reconciliation, return, and disposal at study completion or termination (ICH E6(R2) GCP )
Study drug receipt, labeling, storage, randomization, reconstitution, transfer to study sites, dispensing to subjects, disposal
1International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016). Efficacy Guidelines E6(R2) Integrated Addendum to Good Clinical Practice (GCP). Retrieved from:

3. Drug Accountability More than simply counting pills.
A process to ensure that research participants receive Investigational Product (IP), including the correct study drug, dosage and duration, so that effects seen in the study can be linked to the medication administered.
More than simply counting pills, it should provide a complete accounting of drug handling from receipt through final disposition.
The record keeping associated with the receipt, storage, and dispensation of an investigational product is known as study drug accountability.
The FDA has listed drug accountability as number 3 in a list of top 5 pitfalls.

4. National Institute on Drug Abuse (NIDA) NDAT Clinical Trials Network (CTN)
Multi-site, multi-protocol network to study interventions for the treatment of substance use disorders
The Emmes Corporation has a contract to serve as the Data and Statistics Center (DSC) and Clinical Coordinating Center (CCC) for the network
One of the things we’ve found is that collaboration among our internal group is critical- data manager, clinical trial and regulatory specialists, CRAs, statisticians, programmers, safety and medical monitors- all work together to streamline these processes…

5. IP (Investigational Product) Management and Coordination Challenges in multi-site trials
Determining when to Manufacture and Supply
Licensing- medical licenses, DEA registrations in studies with controlled substances
Medication Storage
Maintaining Adequate On-Site Study IP
Appropriate Use and Documentation of IP Use
End of Study- IP Disposition Procedures

6. The Emmes solution for License Monitoring: Upcoming Expiration Date Notifications
Regulatory Tracking System- monitors expiration date for all medical licenses, DEA registrations, and other important regulatory documents
CRO or site staff can receive notifications at 60, 45, 30, 15 and 2 days prior to document expiration
Report showing all person level documents updated daily

7. The Emmes Solution for Maintaining Supply: Automatic Monitoring of Drug Supply & Distribution
For blinded studies, IP is assigned and monitored directly in the EDC system
During enrollment, treatment and treatment kit (which contains all drug to be used for a participant) are assigned
Flexible – different drug numbers can be assigned for each visit. Used if there are varying doses or drugs throughout a study
Drug kit assigned during enrollment. Drug kits contain all medication to be administered throughout a study.
Populated

8. Automatic Monitoring of Drug Supply & Distribution
The EDC integrated component reviews the inventory and expiration dates nightly at each site and automatically sends resupply requests to the central pharmacy

9. For Unblinded Studies: A centralized medication and supply inventory tracking and reordering process
Inventory eCRF completed by site
SAS program
Creates inventory report
Creates reorder report
Emmes staff submit order to vendor
Sites complete weekly inventory CRF in EDC capturing Inventory and expiration date
Can’t completely automate some supplies due to inventory types and use that isn’t always captured on eCRFs
Urine drug screens
Pregnancy tests
Lab kit shippers
We track this way FOR UNBLINDED STUDIES
Lauren comment: When i did this part of a presentation in an earlier SCT, it was asked why not all supplies can be tracked automatically - removing the need for this CRF process in the first place. I would recommend adding info about that.

10. Inventory and Reorder Report
Inventory data from all sites is populated into a combined inventory report, and supplies below a predetermined threshold are populated into a re-order spreadsheet.
Current & past 4 weeks Inventory
Expiring items and quantities below threshold are highlighted
Thresholds can be site and protocol specific
Current Inventory & past 4 weeks
Expiration dates and quantity below threshold highlighted
Thresholds can be site and protocol specific
Reorder report
Inventory Report
Takes care of Supply hoarding and last minute requests that occur with manual reordering process
Enrollment rate fluctuations across sites and over time
Highlight the fact that it’s predetermined thresholds- is site based, can change manually and at any time…

11. The Emmes Solution for Maintaining Proper IP Procedures- Clear Dispensing Documentation
Participant medication logs were developed to track the administration of study drug to participants depending on the arm of the study- date, amount, dose.

12. The Emmes Solution for Maintaining Proper IP Procedures- Clear Dispensing Documentation
Paper Logs
Paper logs important too- real time, source doc… when don’t do direct data entry…
Participant medication logs were developed to track the administration of study drug to participants depending on the arm of the study.
The shaded lines are those weeks when dispensing was not expected, but sometimes occurred. This is an easy visual way to make sure that you are recording on the correct line.
We also created space for dose adjustments and allowed for replacement doses at the discretion of the Study Physician on page 2 of the log
Have this in the system too- but manual records at the site are helpful when not doing direct data entry- they are the source document, provide the real time information…

13. Quality Assurance (QA) in IP Accountability
Based on GCP guidelines, site monitors review:
IP and shipping records to ensure they are on file before the study begins (ICH (E6) GCP 8.2) and accountability procedures are adequate for study conduct (ICH (E6) GCP 6.4.7).
IP documentation during the trial to ensure that IP has been used according to the protocol (ICH (E6) GCP ).
After trial completion for the final accounting of IP, including drug received, dispensed, returned, and destroyed (ICH (E6) GCP 8.4).

14. Take away messages…
Drug Management and Drug Accountability are required based on GCP guidelines and other regulatory standards
Drug management has a lot of moving parts and can be complex- leverage resources
Plan for drug accountability early in the development phase of the study; effort up front may save time in the end
Leverage resources- What is unusual about our process is that literally everyone is involved, including statisticians and programmers. When speaking it may be worth actually listing out the CCC and DSC staff involved (protocol specialists, monitors, data managers, programmers and statisticians - & others I am probably forgetting).
Everyone is involved, from the sponsor to the Lead Node, CCC/DSC, and the research site staff
Drug management has a lot of moving parts and can be complex
Plan for drug accountability early in the development phase of the study; putting more time and effort up front may save time in the end and result in a better study (safety, efficiency, protocol adherence, etc.)
Don’t remake the wheel; there are tools out there that can be used when creating drug logs for your study

15. Acknowledgements
This project has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN C and HHSN C, and UG1DA
Thank you to the members of the NIDA CTN CCC and DSC teams.
Thank NIDA for supporting this work

16. Thank you for your participation.