Course Outline

Foundations of Bioequivalence and ICH M13 Guidelines

Module 1: Introduction to Bioequivalence (Prof. Moji Adeyeye)

This module introduces the concept of bioequivalence (BE), emphasizing its role in ensuring therapeutic interchangeability between generic and innovator drugs. Topics include the definition of BE, key pharmacokinetic parameters (AUC, Cmax, Tmax), and its importance for oral immediate-release, modified-release, and critical-use medicines. The module highlights NAFDAC’s regulatory approach in Nigeria, including mandates for BE data in marketing authorizations, oversight of Contract Research Organisations (CROs), and the impact of BE on public health, affordability, and patient safety.

Module 2: Overview of ICH M13A and M13B Guidelines (Dr. Hong Lu)

This module provides an in-depth overview of the ICH M13 guideline series, focusing on M13A (Step 5) and M13B (Step 3). M13A addresses BE studies for immediate-release solid oral dosage forms, covering study design, data analysis, and risk-based study conditions (fasting vs. fed). M13B explores biowaivers for additional strengths, focusing on dose proportionality and dissolution testing. The module discusses global harmonization of BE standards, reducing redundant studies, and introduces the roadmap for M13C on complex BE scenarios.

Module 3: Concept of Bioavailability (Dr. Daniel Campos)
This module explores bioavailability (BA) as the foundation of bioequivalence, defining it as the rate and extent of drug absorption into the bloodstream. It covers absolute and relative BA, factors affecting BA (e.g., BCS classification, formulation, metabolism), and examples like ticagrelor (36% BA) and levofloxacin (90% BA). The module links BA to clinical outcomes and regulatory assessments, aligning with ICH M13A standards for harmonized BE studies.

Module 4: Study Design and Sample Size (Dr. Daniel Campos)
This module delves into the fundamentals of BE study design, focusing on ICH M13A recommendations for randomized, single-dose, two-period crossover designs with adequate washout periods. It covers pharmacokinetic parameters (Cmax, Tmax, AUC), the 80–125% acceptance range for BE, and sample size determination based on intra-subject variability, power (80–90%), and test/reference ratios. Case studies on levocetirizine and clonazepam illustrate practical applications, with tools like FARTSSIE for sample size estimation.

Advanced Study Design, Bioanalytics, and Statistical Analysis

Module 5: Deep Dive on Study Design – Part 2 (Eric Owusu)
This module focuses on standardizing BE studies to minimize variability, covering participant selection, food intake (e.g., high-fat meals for fed studies), and physical activity controls. It discusses the use of healthy volunteers, batch size requirements (minimum 100,000 units or 1/10 production scale), and justification for different strengths via dissolution profiles. For fixed-dose combinations (FDCs), the module emphasizes evaluating all active ingredients with validated methods and statistical rigor.

Module 6: Bioanalytical Method Validation for BE Studies (Dr. Hong Lu)
This module explores bioanalytical method validation per ICH M10 guidelines, focusing on chromatographic and ligand binding assays. Key parameters include selectivity, specificity, accuracy, precision, stability, calibration range, matrix effects, and carry-over. It addresses additional considerations like dilution integrity, reinjection reproducibility, cross-reactivity, and hook effects, as well as partial and cross-validation requirements. The module underscores the importance of validation for reliable data in BE studies.

Module 7: Bioanalytical Sample Analysis and Reporting for BE Studies (Eric Owusu)
This module details the prerequisites and procedures for bioanalytical sample analysis in BE studies, per ICH M10. It covers the structure of bioanalytical runs (blanks, calibration standards, QC samples), accuracy requirements, and the importance of Incurred Sample Reanalysis (ISR) with ±20% acceptance criteria. The module outlines reporting requirements, including bioanalytical reports, chromatograms, and run summaries, and highlights common issues like method validation failures and deviations.

Module 8: Biostatistical Considerations in BE Studies (Eric Karikari-Boateng)
This module focuses on statistical methods for BE studies, emphasizing log-transformed Cmax and AUC analysis using the Two One-Sided t-Test (TOST) to ensure the 90% confidence interval falls within 80–125%. It covers ANOVA for variability assessment, AUCt/AUC∞ ratios for sampling adequacy (≥0.80), and case studies (e.g., risperidone with sorbitol) to illustrate formulation impacts on BE. The module stresses the role of statistics in ensuring consistent drug exposure.

Module 9: Case Studies in Bioequivalence (Fredrick Esseku, PhD)
This module presents two real-world BE case studies. Case Study 1 examines an FDC of lamivudine, zidovudine, and nevirapine, highlighting issues with nevirapine’s sampling duration due to its long half-life. Case Study 2 compares ezetimibe tablets in Japanese males, using HPLC-MS and dissolution studies. Key takeaways include the importance of proper training, protocols, extended sampling for long half-life drugs, and stakeholder coordination for reliable BE data.

Regulatory Frameworks, Biowaivers, and Data Integrity

Module 10: Bioequivalence Study Report Assessment and BTIF (Dennis Ake & Eric Owusu)
This module covers the Bioequivalence Trial Information Form (BTIF), a critical component of drug registration dossiers. It details the BTIF structure, including study summaries, clinical design, subject demographics, protocol deviations, safety/efficacy evaluations, analytical methods, and quality assurance. The module emphasizes submission requirements in CTD Module 1 (Word and PDF formats) and provides guidance on pharmacokinetic and statistical reporting for regulatory review.

Module 11: Biowaiver Based on BCS (Dr. Hong Lu)
This module explains the Biopharmaceutics Classification System (BCS) and its application in granting biowaivers for BE studies. It covers BCS Classes I and III eligibility, solubility (highest dose in ≤250 mL, pH 1.2–6.8) and permeability (≥85% absorption) criteria, and rapid/similar dissolution requirements (≥85% in ≤30 mins, f2 ≥50). The module highlights exclusions (e.g., narrow therapeutic index drugs) and the use of in vitro dissolution to predict in vivo absorption.

Module 12: Regulatory Framework for Bioequivalence Data Submission (Dennis Ake)
This module outlines Nigeria’s regulatory framework for BE studies, based on the NAFDAC Act and Bioavailability/Bioequivalence Regulations (2004, draft 2024). It covers study requirements, BTIF reporting, comparator product selection, BCS-based biowaivers, and CTD submission formats. The module emphasizes compliance with clinical trial regulations, investigator qualifications, and NAFDAC’s commitment to ensuring the safety, efficacy, and quality of generic medicines.

Module 13: Data Integrity in BE Studies – Tools and Methods (Eric Owusu & Dennis Ake)
This module addresses data integrity challenges in BE studies, focusing on sponsor responsibilities under ICH GCP. It covers quality assurance/control systems, red flags (e.g., missing documents, implausible data), root causes (e.g., poor training, deliberate manipulation), and inspection triggers (e.g., protocol non-compliance). Recommendations include strengthening QA/QC, ensuring transparency/traceability, and addressing training gaps to maintain trust in BE data.

Learning Outcomes:
Upon completing this course, participants will:

1. Understand the principles of bioequivalence and bioavailability in drug development.
2. Apply ICH M13 guidelines to design, conduct, and analyze BE studies for immediate-release oral dosage forms.
3. Evaluate bioanalytical methods, statistical approaches, and data integrity in BE studies.
4. Navigate regulatory frameworks and submission requirements for BE data in Nigeria and West Africa.
5. Assess the applicability of BCS-based biowaivers and address practical challenges through case studies.

Assessment Methods:

• Quizzes on key concepts (e.g., BE parameters, BCS criteria).
• Case study analysis and group discussions.
• Practical exercises on study design, sample size calculation, and BTIF preparation.
• Final presentation on a mock BE study protocol and dossier submission.

Course Materials:

• ICH M13A and M13B guideline documents.
• Case study handouts and bioanalytical validation templates.
• NAFDAC regulatory guidelines and BTIF forms.
• Supplementary Q&A documents for M13A implementation.

Course Facilitators:

• Prof. Moji Adeyeye (NAFDAC)
• Dr. Hong Lu (ICH Expert)
• Dr. Daniel Campos (Bioavailability Expert)
• Eric Owusu (Ghana FDA)
• Eric Karikari-Boateng (Biostatistics Expert)
• Fredrick Esseku, PhD (Case Study Expert)
• Dennis Ake (NAFDAC Regulatory Expert)

This course equips participants with the knowledge and skills to conduct robust BE studies, ensuring compliance with global and regional regulatory standards while advancing access to safe and effective generic medicines

Course Modules

1. Introduction to ICH and Clinical Trial Harmonization
   • Overview of the International Council for Harmonisation (ICH), its mission, and its impact on global regulatory standards.
   • Key ICH guidelines (Quality, Safety, Efficacy, Multidisciplinary) and their role in clinical research.
2. ICH E6(R3) Guideline Development and Structure
   • Evolution from E6(R2) to E6(R3), including the rationale for updates.
   • Core principles: Ethical conduct, participant safety, scientific validity, and data integrity.
   • Emphasis on Quality by Design (QbD) and risk-proportionate approaches.
3. Designing and Analyzing Clinical Trials
   • Application of the Design, Analyze, Communicate (DAC) framework.
   • Tools like the DAC Assessment Tool (DAT) and NAFDAC’s e-CTAP platform for trial informativeness.
4. Roles and Responsibilities in Clinical Trials
   • Sponsor responsibilities: Trial design, oversight, and risk-based monitoring.
   • Investigator duties: Participant safety, protocol compliance, and data integrity.
   • Ethics Committees (ECs): Ethical review, informed consent oversight, and participant protection.
5. Essential Records and Data Governance
   • Dynamic documentation practices under E6(R3).
   • Data governance frameworks: Ensuring availability, usability, integrity, and security of trial data.
6. Regulatory and Ethical Oversight
   • Role of National Regulatory Authorities (e.g., NAFDAC): Protocol review, GCP compliance, and inspections.
   • Ethical challenges in low-resource settings and strategies for equitable research participation.
7. Key Updates in E6(R3) vs. E6(R2)
   • Streamlined GCP principles (13 to 11).
   • Modernized informed consent (remote/multimedia tools).
   • Enhanced flexibility for decentralized trials and innovative designs.
8. Case Studies and Practical Applications
   • Analysis of real-world GCP violations (e.g., expired comparators, protocol deviations).
   • Lessons on risk management, corrective actions (CAPA), and regulatory consequences.
9. Serious Non-Compliance and Issue Management
   • Identifying and addressing deviations impacting participant safety or data reliability.
   • TransCelerate’s framework for classifying and escalating critical issues.
10. Annex 2: Innovative Trial Designs and Data Sources
    • Guidance on trials using DHTs, RWD, and decentralized models.
    • Proportional oversight strategies for hybrid or remote trials.

Learning Outcomes

By the end of the course, participants will:

• Understand the principles and structure of ICH E6(R3) and its differences from E6(R2).
• Apply risk-based approaches to trial design, monitoring, and documentation.
• Recognize the roles of sponsors, investigators, and regulators in ensuring GCP compliance.
• Navigate ethical and regulatory challenges in diverse clinical trial settings.
• Leverage modern technologies and flexible designs to enhance trial efficiency without compromising quality.

Target Audience

• Clinical researchers, sponsors, and investigators.
• Regulatory affairs professionals and ethics committee members.
• Data managers, monitors, and quality assurance personnel.
• Professionals involved in global clinical trial operations.

COURSE INSTRUCTORS

Prof. Mojisol Christianah Adeyeye PhD, FAAPS, FAS, FNAPharm

Director-General, National Agency for Food & Drug Administration and Control (NAFDAC)

David R. Schoneker

President/Owner of Black Diamond Regulatory Consulting, LLC

Prof. Joseph Fortunak

Professor of Chemistry and Pharmaceutical Science at Howard University, USA,
co-developed a post graduate and Msc .in Regulatory Science.

Prof. Adeboye Adejare

Professor of Pharmaceutical Science at the Philadelphia college of Pharmacy

Dr. Christian Moreton Ph.D

Consultant and adviser of services in formulation and process design, development and
scale up in excipients for over 20 years and Partner, FinnBrit Consulting, Waltham, MA, USA

Dr. Patrick Lukulay

Founder and President of Technology Solutions for Global Health,
a consultancy firm based in Ghana

Hong Shen, Ph.D.

Senior Vice President and Head of China Innovation Center of Roche (CICoR)

Dr. Nkere K. Ebube, Ph.D., FPSN, FNAPharm, FNAPPSA

Senior Director, Technical and Analytical Operations at TerSera Therapeutics, Illinois, USA

Jared R. Auclair, Ph.D.

Vice Provost, Research Economic Development and Director of Bio-innovation
in the Office of the Provost at Northeastern University

Dr Trevor Laird

Managing Director: Trevor Laird Associates Ltd (UK)