Bioequivalence stud slides CROs BE Study Operational and Admin

1. RBEC BE Study Admin and Ops
Amha Kebede
Senior Advisor, MoH/AHRI
Addis Ababa, Ethiopia, April 27-29, 2023

2. Outline
• Background
• Historical , the RBEC pivotal/pilot study experience
• CROs organizational
• Study protocol and subject admin
• Test sample shipment and handling
• Study ops and facility/site management
• Contract, collaboration, and Soliciting sponsors
• Report and regulatory
• Change and future
• Summary/conclusion
• Reference

3. Background
• Regional Bioequivalence Centre (RBEC)
• Established in 2012
• Feasibility study ( 2009)
• Sch of Pharmacy (Bioanalytic) & AHRI (CT)
• PPP
• CRO
• East African pharmaceutical manufacturers

4. Background…
First pilot study:
Title: Bioequivalence study of oral ciprofloxacin tablets after single dose
administration of Strox oral 500 mg tablet.
Subjects: 12 healthy individualts (fasting)
Comparator: Ciprobay® (Bayer HealthCare Pharma Inc., Germany)
Sponsor: Universal Corporation Ltd., Kenya
Second pilot study:
Title: Bioequivalence study of oral Co-trimoxazole (80 mg Trimethoprim / 400
mg Sulfamethoxazole) after single dose administration of COTRI tablets.
Subjects: 12 healthy subjects under fasting conditions
Comparator: BACTRIMTM (Hoffmann-La Roche Inc.)
Sponsor: Addis Pharmaceutical Factory PLC, Ethiopia

5. Background…
Pivotal study:
Title: Bioequivalence study of Ciprofloxacin HCl 500mg Tablets after oral single
dose administration of Ciproxin tablet.
Subjects: In 24 healthy subjects under fasting conditions.
Comparator: Ciprobay® (500 mg Ciprofloxacin HCl tablet, Bayer Health Care
Pharmaceuticals Inc., Germany)
Sponsor: East African Pharmaceuticals Plc, Ethiopia

6. REBC Organization
Admin & functional structure:
• Governing board
• Adequate staff (4)
• Strategic plan
• Various SOPs
Key Personnel :
• Bioanalytical Service
• Quality Assurance
• Clinical Service
Quality management system
• Quality policy
• Regular calibration
• SOP for study design and sample
size
• Bioanalytic lab ISO certified
(17025)
• WHO-PQ pre-inspection

7. Infrastructure and basic facilities
• Bioanalytical laboratory service
(SoP)
• Clinical study center (AHRI)
• Sample handling and storage unit
• Clean air cabinets
• Temperature & humidity
monitoring system
• Chemical store

8. Testing & analytical equipment
Physicochemical Product
Quality Evaluation
• Dissolution testing
• Disintegration tester
• Tablet hardness tester
• Tablet friability tester
• UV spectroscopy
• Sonicator
• Titration apparatus
Bioanalytical Method and Testing
• HPLC with photodiode array
detector
• LC/MS – MS
• Deep Freezer (-20)
• Ultrasonic cleaner
• Cooling centrifuge
• Fume hood
• Filtration vacuum pump

9. Study protocol & subject admin
• In accordance with the principles of GCP and GLP
• Study protocols reviewed and approved by NEC and EFDA
• Study subjects recruitment & administration conducted in line with GCP principles
 Good Clinical Practice Assessment of Investigator (SOP No.: QA034-00)
• Regular oversite by the study monitor
 Monitoring SOP (QA027-01)
 Monitoring Plan (Form No: RBEC/QF160-01)
 Monitoring Report Form (Form No: RBEC/QF162-01)
 Auditing the Clinic Unit (SOP No.: QA023-01)

10. Test sample shipment and handling
 Investigational Medicinal Products
(IMPs) are received and registered
(Form No: RBEC/QF165-01).
 Handling, storage and shipping
(SOP No.: QA029-01)
 Biological sample collection,
handling, shipping and storage are
also conducted as per GCP and
GLP principles and based on
approved SOPs.
1 Protocol title:
2 Protocol study code:
3 Type of product (Comparator/Test Product):
4 Product name (Brand Name):
5 Source/Sponsor:
6 Batch No.:
7 Expiry date:
8 Dosage form:
9 Pack size:
10 Total quantity received:
11 Condition of samples during receipt:
12 Associated documents received:
13 Received by (sign and date):
14 Storage area at RBEC (Room No.):
15 Responsible person for the store (sign & date):
16 Quantity used by
BAU:
Quality Control Tests:
In-vitro Dissolution Profile:
17 Quantity transferred to Clinic Unit:
18 Transferred (to Clinic Unit) by (sign and date):
19 Quantity of unused items returned from Clinic
Unit:
20 Received (from Clinic Unit) by (sign and date):
21 Quantity returned to Sponsor, if any:
22 Returned (to Sponsor) by (sign and date)
23 Quantity destructed at RBEC, if any:
24 Destructed by (sign and date):
25 Additional Remarks, if any
__________________________ _____________ _____________
[Study Management Manager] [Signature] [Date]
IMP Record Form

11. Study ops and facility/site management
• The clinical site managed by AHRI (CTD)
• 12 beds
• Clinicians
• Nurses
• Lab techs
• The bioanalytic lab managed by AAU Sch of Pharmacy (RBEC)
• ISO certified (17025)
• WHO-PQ pre-inspection

12. Contract, Collaboration, & Soliciting sponsors
• “Bioequivalence Tripartite Contract Agreement” SOP (SOP No.: QA025-01)
• “Tripartite Contract Agreement” Form (Form No: RBEC/QF158-01)
 RBEC, the clinical study center and the sponsor
• Contract Agreement with Monitor (Form No: RBEC/QF159-01, Ref. SOP No.
QA026-01)
• Contract agreement with sponsor (Form No: RBEC/QF030-01, Ref. SOP No.
QA005-01)
• Developed a Business Plan [2018-2023]:
 Partnership and collaboration
 Service expansion and customer satisfaction
 Financial management and revenue generation
 Customers and competitor profiling

13. Report and regulatory
• RBEC :
 Registered by the Ethiopian Investment Commission (EIC)
 Licensed by EFDA
 Has an approved CRO master file
• The bioanalytics laboratory was accredited by ENAO
• Pharmacokinetic analysis was made using SAS® and WinNonlin ®
• Reporting of BE studies were made according to contracts and regulatory
requirements
 Bioequivalence Safety Report Form
 Care Report Form/Adverse event reporting form

14. Challenges
• MoH’s limited involvement
• Regulatory enforcement
• Lack of clear institutional organization
• Political commitment
• Funding/finance
• Low production capacity
• Willingness to access the BE center

15. Change and future
• MOH : better coordination
• AHRI’s new mandate
• Minimum or affordable service
• Clarity of ownership
• Clear business plan
• Strong monitoring and evaluation system

16. Summary/conclusion
• Clarity for institutional organization
• Governance should be clearly defined
• Need for clear business plan
• The business model should suite the country’s context
• A roadmap should be prepared to predict the future
• Market incentive or price protection incentive
• Governments & key stakeholders' vital (Viability)
• Regional harmonization and inter-continental free trade agreement

17. Reference and Resource
1. Capacity Assessment of the Regional Bioequivalence Center (March,
2023)
2. Challenges and prospects of regional bioequivalence study initiative
in Ethiopia: a qualitative study (AAU, MSc thesis, 2020)
3. National strategy and plan of action for pharmaceutical
manufacturing development in Ethiopia (2015–2025)
4. Study on the Feasibility of Conducting Bioequivalence Studies in
East Africa (GTZ, 2009)