Contents
First 2 lectures (Sofjia’s notes)..................................................................................................................................................................................................... 3
THE DRUG LIFE CYCLE .......................................................................................................................................................................................................... 3
PHENOTYPIC VS. TARGET-BASED DRUG DISCOVERY ............................................................................................................................................................. 4
ASSAYS IN ANTITUMORAL DRUG DISCOVERY ........................................................................................................................................................................ 4
PREDICTIVE VALIDITY AND TRANSLATABILITY......................................................................................................................................................................... 5
FROM HIT TO LEAD ................................................................................................................................................................................................................ 5
DISCOVERY TESTING IN TDD ................................................................................................................................................................................................. 6
ADME AND SAFETY TESTING.................................................................................................................................................................................................. 6
PHARMACOLOGICAL PROFILING .......................................................................................................................................................................................... 7
PHARMACEUTICAL DEVELOPMENT: FROM PREFORMULATION TO ADVANCED DRUG DELIVERY SYSTEMS .................................................................................... 7
ACTIVE PHARMACEUTICAL INGREDIENT (API) VS. DRUG PRODUCT ........................................................................................................................................ 7
PHASES OF PHARMACEUTICAL DEVELOPMENT ..................................................................................................................................................................... 8
DEVELOPMENTAL HURDLES FOR ORAL ADMINISTRATION ................................................................................................................................................ 8
PREFORMULATION: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL CHARACTERIZATION ................................................................................................... 9
IONIZATION BEHAVIOR (pKa, pKb) .................................................................................................................................................................................. 11
PARTITION COEFFICIENT (Log P) AND DISTRIBUTION COEFFICIENT (Log D) ..................................................................................................................... 12
SOLID STATE PROPERTIES OF THE AP .................................................................................................................................................................................. 13
CHEMICAL STABILITY OF THE API ................................................................................................................................................................................... 15
PERMEABILITY AND ABSORPTION POTENTIAL................................................................................................................................................................. 15
FORMULATION AND PROCESS DEVELOPMENT .................................................................................................................................................................... 17
IMMEDIATE RELEASE TABLETS ........................................................................................................................................................................................ 18
SUSPENSIONS .............................................................................................................................................................................................................. 20
CREAMS AND OINTMENTS ............................................................................................................................................................................................. 21
CLINICAL DRUG DEVELOPMENT ............................................................................................................................................................................................... 27
DEFINING CLINICAL RESEARCH VS. CLINICAL TRIALS ......................................................................................................................................................... 27
THE DRUG DEVELOPMENT PROCESS – MOVING FROM NON-CLINICAL TO CLINICAL ............................................................................................................ 28
NON-CLINICAL SAFETY STUDIES – REQUIREMENTS BEFORE FIH (ICH M3(R2) GUIDELINE) .................................................................................................... 28
ENDPOINTS OF NON-CLINICAL SAFETY STUDIES ........................................................................................................................................................... 29
MINIMAL ANTICIPATED BIOLOGICAL EFFECT LEVEL (MABEL) – PHARMACOLOGICAL APPROACH ..................................................................................... 31
PHASE I CLINICAL TRIALS – DEFINITION AND CHARACTERISTICS ......................................................................................................................................... 32
PHASE I TRIAL DESIGNS ...................................................................................................................................................................................................... 33
LATER PHASE I STUDIES (STILL IN HEALTHY VOLUNTEERS, BUT LATE IN DEVELOPMENT) ....................................................................................................... 34
PHARMACEUTICAL MEDICINE: CLINICAL DRUG DEVELOPMENT – PART 2 .................................................................................................................................. 34
TRANSITION FROM PHASE I TO PHASE II – THE CRITICAL DECISION POINT ........................................................................................................................... 34
PHASE II STUDY CHARACTERISTICS ..................................................................................................................................................................................... 35
CLINICAL DRUG DEVELOPMENT: PHASE III TO POST-MARKETING SURVEILLANCE ..................................................................................................................... 39
TRANSITION FROM EXPLORATORY TO CONFIRMATORY PHASE ............................................................................................................................................. 39
PHASE III CLINICAL TRIALS .................................................................................................................................................................................................. 39
THE CLINICAL TRIAL PROTOCOL - FUNDAMENTAL ELEMENTS .............................................................................................................................................. 40
CLINICAL TRIAL ENDPOINTS .......................................................................................................................................................................................... 40
STUDY DESIGNS - RANDOMIZED CONTROLLED TRIALS (RCTs) ........................................................................................................................................ 42
PARALLEL GROUP VS. CROSSOVER DESIGN ................................................................................................................................................................... 43
VALIDITY IN CLINICAL TRIALS .............................................................................................................................................................................................. 44
POST-MARKETING SURVEILLANCE, AND ALTERNATIVE APPROACHES........................................................................................................................................ 47
PHASE IV – POST-MARKETING SURVEILLANCE ..................................................................................................................................................................... 47
Pharmacovigilance ........................................................................................................................................................................................................ 47
ALTERNATIVE APPROACHES TO CLASSICAL DRUG DEVELOPMENT....................................................................................................................................... 48
Why Change the Classical Approach? ............................................................................................................................................................................. 48
APPROACH 1: EXPLORATORY CLINICAL TRIAL APPLICATION (eCTA) / PHASE ZERO .......................................................................................................... 48
APPROACH 2: BIOMARKERS AND CHALLENGE TRIALS .................................................................................................................................................... 49
APPROACH 3: MASTER PROTOCOLS............................................................................................................................................................................... 50
CLINICAL DRUG DEVELOPMENT: STUDY DESIGNS, HIERARCHY OF EVIDENCE, AND MODERN TRIAL TYPES ............................................................................... 51
OVERVIEW OF STUDY DESIGN HIERARCHY .......................................................................................................................................................................... 51
DESCRIPTIVE STUDY DESIGNS ....................................................................................................................................................................................... 51
ANALYTICAL OBSERVATIONAL STUDY DESIGNS .............................................................................................................................................................. 52
RANDOMIZED CONTROLLED TRIAL (RCT) ....................................................................................................................................................................... 54
SECONDARY RESEARCH – SYSTEMATIC REVIEWS AND META-ANALYSES ......................................................................................................................... 55
STUDY CLASSIFICATION CRITERIA (SUMMARY) .................................................................................................................................................................... 55
MODERN RCT CLASSIFICATIONS – EXPLANATORY VS. PRAGMATIC.................................................................................................................................. 56
MODERN RCT CLASSIFICATIONS – CENTRALIZED VS. DECENTRALIZED VS. VIRTUAL............................................................................................................. 57
CLINICAL DRUG DEVELOPMENT: SPECIAL POPULATIONS ......................................................................................................................................................... 59
INTRODUCTION – WHY SPECIAL POPULATIONS MATTER ...................................................................................................................................................... 59
PEDIATRICS – THE CHILD IS NOT A SMALL ADULT ................................................................................................................................................................. 59
Developmental Pharmacokinetics (Same Dose, Different Concentration) .............................................................................................................................. 60
Absorption..................................................................................................................................................................................................................... 60
Distribution ................................................................................................................................................................................................................... 62
Clearance (Metabolism and Excretion)............................................................................................................................................................................ 62
PREGNANCY AND LACTATION ............................................................................................................................................................................................. 64
GERIATRICS (ELDERLY PATIENTS)......................................................................................................................................................................................... 66
CHRONIC KIDNEY DISEASE (CKD) AND CHRONIC LIVER DISEASE (CLD)............................................................................................................................... 66
PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING AND SIMULATION ............................................................................................................... 67
1
, TOP-DOWN VS. BOTTOM-UP MODELING ............................................................................................................................................................................. 67
BIOSIMULATION AND MODEL-INFORMED DRUG DEVELOPMENT (MIDD) .............................................................................................................................. 68
PBPK MODELING – DEFINITION AND PRINCIPLES ................................................................................................................................................................ 68
Comparison with Other PK Modeling Approaches ................................................................................................................................................................. 69
Mechanistic Resolution – Different Models for Different Organs ............................................................................................................................................ 70
Components of a PBPK Model (Panel B of the key figure) ....................................................................................................................................................... 70
APPLICATIONS OF PBPK MODELING .................................................................................................................................................................................... 71
CASE STUDY ....................................................................................................................................................................................................................... 72
PBPK IN PEDIATRIC POPULATIONS ...................................................................................................................................................................................... 77
MODEL-INFORMED DRUG DEVELOPMENT (MIDD) – COMPREHENSIVE LECTURE NOTES............................................................................................................ 79
Defining MIDD..................................................................................................................................................................................................................... 80
CASE STUDY 1 – CAPLACIZUMAB (CABLIVI®) ........................................................................................................................................................................ 81
PART 3: CASE STUDY 2 – OCRELIZUMAB (OCREVUS®) ........................................................................................................................................................... 84
THE CORE PRINCIPLES OF MIDD (THE "ABCs") ..................................................................................................................................................................... 88
GUIDELINES AND REGULATIONS IN CLINICAL RESEARCH......................................................................................................................................................... 89
THE NUREMBERG CODE (1947) ........................................................................................................................................................................................... 89
THE DECLARATION OF HELSINKI (1964) ............................................................................................................................................................................... 90
PART 4: ICH-GOOD CLINICAL PRACTICE (GCP) GUIDELINES (1997) ...................................................................................................................................... 91
THE EUROPEAN CLINICAL TRIAL DIRECTIVE (CTD, 2001) ...................................................................................................................................................... 92
THE BELGIAN LAW OF 7 MAY 2004 ....................................................................................................................................................................................... 92
DIFFERENCES BETWEEN SMALL MOLECULES AND BIOLOGICALS ............................................................................................................................................. 94
BIOLOGICALS – Definition ................................................................................................................................................................................................... 95
CLASSES OF BIOLOGICALS ................................................................................................................................................................................................. 95
ANTIBODIES ....................................................................................................................................................................................................................... 96
I. MODE OF ACTION – WHAT'S DIFFERENT IN THE ACTIVITY OF ANTIBODIES? .................................................................................................................. 97
II. PHARMACOKINETICS ................................................................................................................................................................................................. 99
III. SAFETY – WHAT'S DIFFERENT IN SAFETY OF BIOLOGICALS? ..................................................................................................................................... 101
IV. CLINICAL DEVELOPMENT – WHAT'S DIFFERENT? ..................................................................................................................................................... 102
VACCINE DEVELOPMENT ....................................................................................................................................................................................................... 106
WHAT IS A VACCINE? ........................................................................................................................................................................................................ 106
WHY DEVELOP VACCINES? .......................................................................................................................................................................................... 107
HOW VACCINES WORK................................................................................................................................................................................................ 107
TYPES OF VACCINES .................................................................................................................................................................................................... 107
Preclinical and Clinical Vaccine Development .................................................................................................................................................................... 110
PHARMACOVIGILANCE ................................................................................................................................................................................................ 111
OBSTACLES IN VACCINE DEVELOPMENT ........................................................................................................................................................................... 112
THERAPEUTIC VACCINES .................................................................................................................................................................................................. 113
IMPLEMENTATION AND RECOMMENDATIONS.................................................................................................................................................................... 113
PHARMACOVIGILANCE .......................................................................................................................................................................................................... 114
DEFINITIONS .................................................................................................................................................................................................................... 114
PRE-REGISTRATION / GCP REQUIREMENTS REGARDING PHARMACOVIGILANCE ............................................................................................................... 114
KEY DEFINITIONS FOR SAFETY REPORTING .................................................................................................................................................................. 115
CAUSALITY ASSESSMENT .................................................................................................................................................................................................. 116
Possible Consequences ............................................................................................................................................................................................... 117
GCP/LEGAL OBLIGATIONS FOR PHARMACOVIGILANCE IN CLINICAL TRIALS ...................................................................................................................... 117
PRE- AND POST-MARKETING ............................................................................................................................................................................................. 119
PHARMACEUTICAL MEDICINE: REGULATION CONCERNING MARKETING AUTHORIZATION (EU AND BELGIAN CONTEXT) ......................................................... 122
MARKET, PATIENT ACCESS, AND SOCIETAL PERSPECTIVE .................................................................................................................................................. 122
COMMON TECHNICAL DOCUMENT (CTD) ......................................................................................................................................................................... 126
ORPHAN MEDICINES ........................................................................................................................................................................................................ 127
CONDITIONAL MARKETING AUTHORIZATION (CMA) ..................................................................................................................................................... 128
MEDICINE PRICING AND REIMBURSEMENT ............................................................................................................................................................................ 131
HEALTH ECONOMIC INSTRUMENTS .................................................................................................................................................................................. 131
PRICING OF INNOVATIVE MEDICINES ................................................................................................................................................................................ 132
MANAGED ENTRY AGREEMENTS (MEAs) ............................................................................................................................................................................ 133
HEALTH SYSTEMS ................................................................................................................................................................................................................... 136
HEALTH SYSTEM ............................................................................................................................................................................................................... 136
WHO FRAMEWORK FOR HEALTH SYSTEM PERFORMANCE ASSESSMENT............................................................................................................................ 137
HISTORICAL EVOLUTION OF HEALTH SYSTEMS .................................................................................................................................................................. 138
TYPOLOGY AND CLASSIFICATION OF HEALTH SYSTEMS ..................................................................................................................................................... 140
DRUGS AND SOCIETY (PART I)................................................................................................................................................................................................. 143
FROM CHEMICAL COMPOUND TO TREATMENT.................................................................................................................................................................. 143
Drugs Can Be Used for Different Actions ....................................................................................................................................................................... 144
NOMENCLATURE OF DRUGS ............................................................................................................................................................................................. 144
REGISTERED DRUGS ON THE BELGIAN MARKET................................................................................................................................................................. 145
DANGER OF BRAND NAMES: SOUND-ALIKE AND LOOK-ALIKE (LASA) ............................................................................................................................ 146
INDICATIONS OF DRUGS................................................................................................................................................................................................... 146
UNIT DOSE PACKAGING AND IDENTIFICATION................................................................................................................................................................... 147
COLD CHAIN MANAGEMENT ............................................................................................................................................................................................. 147
QUALITY STANDARDS FOR DRUGS AND RAW MATERIALS ................................................................................................................................................... 147
PRESCRIPTION OF DRUGS ................................................................................................................................................................................................ 149
DRUG FORMULARY IN HOSPITALS ..................................................................................................................................................................................... 150
2
, DRUG DISTRIBUTION ........................................................................................................................................................................................................ 151
Information on Drugs......................................................................................................................................................................................................... 153
Drug Treatment – Compliance / Adherence......................................................................................................................................................................... 153
THE MEDICAL DEPARTMENT – AN INDUSTRY PERSPECTIVE ON MEDICINE DEVELOPMENT ....................................................................................................... 153
AI IN DRUG DEVELOPMENT ............................................................................................................................................................................................... 153
The Drug Development Funnel ........................................................................................................................................................................................... 154
GEOGRAPHY OF INNOVATION ........................................................................................................................................................................................... 155
Medical Department in Clinical Development..................................................................................................................................................................... 155
Regulatory Approval – A European Effort ....................................................................................................................................................................... 156
Health Technology Assessment (HTA) and Reimbursement – A National Effort ..................................................................................................................... 157
Commercialization – A Local Effort..................................................................................................................................................................................... 158
CLOSING REMARKS – THE DRUG LIFE CYCLE AND REWARD BOX ............................................................................................................................................. 158
First 2 lectures (Sofjia’s notes)
KEY TERMINOLOGY
• Generics: copies of small molecules that are chemically identical
• Biosimilars: copies of monoclonal antibodies (mAbs) that are chemically/structurally similar but not identical
• PRIME: Priority Medicines (EMA scheme for drugs with high unmet need)
• Orphan medicines: used for rare diseases
• ATMP: Advanced Therapy Medicinal Product (gene therapy, RNA-based therapies)
• BLA: Biologics License Application (US FDA)
• CTA: Clinical Trial Application (EU)
• CTIS: Clinical Trial Information System (EU portal for clinical trials)
• IND: Investigational New Drug (submitted between preclinical and clinical studies)
• NDA: New Drug Application (US FDA for marketing approval)
• MA(A): Marketing Authorisation (Application) (EU)
• CTD: Common Technical Document (standardized dossier for MA submission)
THREE WAVES OF DRUG DEVELOPMENT
1st Wave (1900s) - Small Molecules
• Symptomatic treatment; dose-dependent selectivity leads to off-target toxicity
• Example: statins target cholesterol synthesis enzyme; adverse effect = skeletal muscle toxicity
2nd Wave (1980s) - Biologicals
• Disease-modifying; target-driven effects → fewer off-target effects
• Example: PCSK9 inhibitors increase LDL-receptor recycling → lower LDL-cholesterol
3rd Wave (2000s) - ATMPs
• Potentially transformational; treat or modulate underlying cause
• Examples: gene therapy, siRNA, mRNA vaccines (e.g., SARS-CoV-2: synthetic mRNA → endogenous production of viral
antigen to induce immune response)
Trends
• Small molecules: decreasingly used
• Biologicals and ATMPs: increasingly used (mAbs, bispecific antibodies that bind two different antigens)
THE DRUG LIFE CYCLE
• Early period: drug discovery and development (preclinical animals + clinical humans) → high financial investment
• Middle period: drug marketed → return on investment
• Late period: loss of market exclusivity (patent expiry) → generics or biosimilars enter market
Approval Pathway
• FIH testing approval: CTA (EU) / IND (submitted between preclinical and clinical)
• Exploratory/early development: preclinical research + phase I/II
• Confirmatory/late development: phase III
• Marketing approval: NDA (US) or MA(A) (EU); CTD is the submission format
• Post-approval: reimbursement, commercialisation
3
, Quality and Ethical Standards
• Quality standards: GLP, GCP, GMP, GDP
• Ethical standards: Nuremberg Code, Declaration of Helsinki
• Regulations: CTR (Clinical Trial Regulation), MDR (Medical Device Regulation), IVDR (In Vitro Diagnostic Regulation)
DRUG DISCOVERY - OVERVIEW
Aim
• Identify pharmacologically active molecules that reach their target in sufficient amounts to produce therapeutic effect
without unacceptable toxicity
Strategic Requirements
• Identify unmet medical need and assess market opportunities and risks
Scientific Requirements
• Suitable disease models, targets, or screening strategies
Operational Requirements
• Sufficient staff, expertise, facilities, and financial resources
Drug Categories
• First-in-class: first drug on market with new mechanism of action
• Fast followers, best-in-class, me-too drugs
PHENOTYPIC VS. TARGET-BASED DRUG DISCOVERY
Phenotypic Drug Discovery (PDD)
• Compounds selected based on observable effects in cells or organisms without prior knowledge of molecular target
• Target-agnostic/unbiased
• Has produced many first-in-class medicines
• Can be done in vivo (ADME testing)
• Disadvantages: lower throughput; difficult to optimise drugs due to lack of initial knowledge about molecular MoA
• Empirical approach
Target-Based Drug Discovery (TDD)
• Dominant since 1990s; aims to identify and modulate specific molecular targets (proteins involved in disease
pathogenesis)
• Advances enabling TDD: RNA interference, high-throughput screening, mAbs, structure-based design (X-ray
crystallography, computational modelling)
• Hypothesis-driven
• Required assumptions: target relevant to human disease; target modulation produces desired effect; preclinical activity
translates to clinical benefit
• Risk: chosen target or MoA may not be sufficiently relevant to disease to provide therapeutic index → high attrition rates
• Structure-based drug design applied once target is known
Analysis of FDA-Approved NMEs (1999-2008)
• 259 NMEs approved; 75 first-in-class drugs
• Among first-in-class small molecule NMEs: more discovered via phenotypic screening than target-based approaches
(despite TDD dominance)
• Overall: 100 NMEs discovered via target-based approaches; biologics are inherently target-based
• Also: 164 follower drugs, 20 imaging agents
• Conclusion: over-reliance on target-based strategies (without sufficient attention to MoA and target relevance) can
reduce R&D productivity
ASSAYS IN ANTITUMORAL DRUG DISCOVERY
In Vitro Antiproliferation Assay (Phenotypic)
• Cancer cells seeded in 96-well plate; compounds added to identify growth inhibitors
• Cell viability measured by MTT assay: living cells convert MTT into dark purple product; dead cells do not
• Higher compound concentration = stronger growth inhibition
• Example: Stellettin identified as antitumoral compound (effective against lung cancer)
4
First 2 lectures (Sofjia’s notes)..................................................................................................................................................................................................... 3
THE DRUG LIFE CYCLE .......................................................................................................................................................................................................... 3
PHENOTYPIC VS. TARGET-BASED DRUG DISCOVERY ............................................................................................................................................................. 4
ASSAYS IN ANTITUMORAL DRUG DISCOVERY ........................................................................................................................................................................ 4
PREDICTIVE VALIDITY AND TRANSLATABILITY......................................................................................................................................................................... 5
FROM HIT TO LEAD ................................................................................................................................................................................................................ 5
DISCOVERY TESTING IN TDD ................................................................................................................................................................................................. 6
ADME AND SAFETY TESTING.................................................................................................................................................................................................. 6
PHARMACOLOGICAL PROFILING .......................................................................................................................................................................................... 7
PHARMACEUTICAL DEVELOPMENT: FROM PREFORMULATION TO ADVANCED DRUG DELIVERY SYSTEMS .................................................................................... 7
ACTIVE PHARMACEUTICAL INGREDIENT (API) VS. DRUG PRODUCT ........................................................................................................................................ 7
PHASES OF PHARMACEUTICAL DEVELOPMENT ..................................................................................................................................................................... 8
DEVELOPMENTAL HURDLES FOR ORAL ADMINISTRATION ................................................................................................................................................ 8
PREFORMULATION: PHYSICOCHEMICAL AND BIOPHARMACEUTICAL CHARACTERIZATION ................................................................................................... 9
IONIZATION BEHAVIOR (pKa, pKb) .................................................................................................................................................................................. 11
PARTITION COEFFICIENT (Log P) AND DISTRIBUTION COEFFICIENT (Log D) ..................................................................................................................... 12
SOLID STATE PROPERTIES OF THE AP .................................................................................................................................................................................. 13
CHEMICAL STABILITY OF THE API ................................................................................................................................................................................... 15
PERMEABILITY AND ABSORPTION POTENTIAL................................................................................................................................................................. 15
FORMULATION AND PROCESS DEVELOPMENT .................................................................................................................................................................... 17
IMMEDIATE RELEASE TABLETS ........................................................................................................................................................................................ 18
SUSPENSIONS .............................................................................................................................................................................................................. 20
CREAMS AND OINTMENTS ............................................................................................................................................................................................. 21
CLINICAL DRUG DEVELOPMENT ............................................................................................................................................................................................... 27
DEFINING CLINICAL RESEARCH VS. CLINICAL TRIALS ......................................................................................................................................................... 27
THE DRUG DEVELOPMENT PROCESS – MOVING FROM NON-CLINICAL TO CLINICAL ............................................................................................................ 28
NON-CLINICAL SAFETY STUDIES – REQUIREMENTS BEFORE FIH (ICH M3(R2) GUIDELINE) .................................................................................................... 28
ENDPOINTS OF NON-CLINICAL SAFETY STUDIES ........................................................................................................................................................... 29
MINIMAL ANTICIPATED BIOLOGICAL EFFECT LEVEL (MABEL) – PHARMACOLOGICAL APPROACH ..................................................................................... 31
PHASE I CLINICAL TRIALS – DEFINITION AND CHARACTERISTICS ......................................................................................................................................... 32
PHASE I TRIAL DESIGNS ...................................................................................................................................................................................................... 33
LATER PHASE I STUDIES (STILL IN HEALTHY VOLUNTEERS, BUT LATE IN DEVELOPMENT) ....................................................................................................... 34
PHARMACEUTICAL MEDICINE: CLINICAL DRUG DEVELOPMENT – PART 2 .................................................................................................................................. 34
TRANSITION FROM PHASE I TO PHASE II – THE CRITICAL DECISION POINT ........................................................................................................................... 34
PHASE II STUDY CHARACTERISTICS ..................................................................................................................................................................................... 35
CLINICAL DRUG DEVELOPMENT: PHASE III TO POST-MARKETING SURVEILLANCE ..................................................................................................................... 39
TRANSITION FROM EXPLORATORY TO CONFIRMATORY PHASE ............................................................................................................................................. 39
PHASE III CLINICAL TRIALS .................................................................................................................................................................................................. 39
THE CLINICAL TRIAL PROTOCOL - FUNDAMENTAL ELEMENTS .............................................................................................................................................. 40
CLINICAL TRIAL ENDPOINTS .......................................................................................................................................................................................... 40
STUDY DESIGNS - RANDOMIZED CONTROLLED TRIALS (RCTs) ........................................................................................................................................ 42
PARALLEL GROUP VS. CROSSOVER DESIGN ................................................................................................................................................................... 43
VALIDITY IN CLINICAL TRIALS .............................................................................................................................................................................................. 44
POST-MARKETING SURVEILLANCE, AND ALTERNATIVE APPROACHES........................................................................................................................................ 47
PHASE IV – POST-MARKETING SURVEILLANCE ..................................................................................................................................................................... 47
Pharmacovigilance ........................................................................................................................................................................................................ 47
ALTERNATIVE APPROACHES TO CLASSICAL DRUG DEVELOPMENT....................................................................................................................................... 48
Why Change the Classical Approach? ............................................................................................................................................................................. 48
APPROACH 1: EXPLORATORY CLINICAL TRIAL APPLICATION (eCTA) / PHASE ZERO .......................................................................................................... 48
APPROACH 2: BIOMARKERS AND CHALLENGE TRIALS .................................................................................................................................................... 49
APPROACH 3: MASTER PROTOCOLS............................................................................................................................................................................... 50
CLINICAL DRUG DEVELOPMENT: STUDY DESIGNS, HIERARCHY OF EVIDENCE, AND MODERN TRIAL TYPES ............................................................................... 51
OVERVIEW OF STUDY DESIGN HIERARCHY .......................................................................................................................................................................... 51
DESCRIPTIVE STUDY DESIGNS ....................................................................................................................................................................................... 51
ANALYTICAL OBSERVATIONAL STUDY DESIGNS .............................................................................................................................................................. 52
RANDOMIZED CONTROLLED TRIAL (RCT) ....................................................................................................................................................................... 54
SECONDARY RESEARCH – SYSTEMATIC REVIEWS AND META-ANALYSES ......................................................................................................................... 55
STUDY CLASSIFICATION CRITERIA (SUMMARY) .................................................................................................................................................................... 55
MODERN RCT CLASSIFICATIONS – EXPLANATORY VS. PRAGMATIC.................................................................................................................................. 56
MODERN RCT CLASSIFICATIONS – CENTRALIZED VS. DECENTRALIZED VS. VIRTUAL............................................................................................................. 57
CLINICAL DRUG DEVELOPMENT: SPECIAL POPULATIONS ......................................................................................................................................................... 59
INTRODUCTION – WHY SPECIAL POPULATIONS MATTER ...................................................................................................................................................... 59
PEDIATRICS – THE CHILD IS NOT A SMALL ADULT ................................................................................................................................................................. 59
Developmental Pharmacokinetics (Same Dose, Different Concentration) .............................................................................................................................. 60
Absorption..................................................................................................................................................................................................................... 60
Distribution ................................................................................................................................................................................................................... 62
Clearance (Metabolism and Excretion)............................................................................................................................................................................ 62
PREGNANCY AND LACTATION ............................................................................................................................................................................................. 64
GERIATRICS (ELDERLY PATIENTS)......................................................................................................................................................................................... 66
CHRONIC KIDNEY DISEASE (CKD) AND CHRONIC LIVER DISEASE (CLD)............................................................................................................................... 66
PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING AND SIMULATION ............................................................................................................... 67
1
, TOP-DOWN VS. BOTTOM-UP MODELING ............................................................................................................................................................................. 67
BIOSIMULATION AND MODEL-INFORMED DRUG DEVELOPMENT (MIDD) .............................................................................................................................. 68
PBPK MODELING – DEFINITION AND PRINCIPLES ................................................................................................................................................................ 68
Comparison with Other PK Modeling Approaches ................................................................................................................................................................. 69
Mechanistic Resolution – Different Models for Different Organs ............................................................................................................................................ 70
Components of a PBPK Model (Panel B of the key figure) ....................................................................................................................................................... 70
APPLICATIONS OF PBPK MODELING .................................................................................................................................................................................... 71
CASE STUDY ....................................................................................................................................................................................................................... 72
PBPK IN PEDIATRIC POPULATIONS ...................................................................................................................................................................................... 77
MODEL-INFORMED DRUG DEVELOPMENT (MIDD) – COMPREHENSIVE LECTURE NOTES............................................................................................................ 79
Defining MIDD..................................................................................................................................................................................................................... 80
CASE STUDY 1 – CAPLACIZUMAB (CABLIVI®) ........................................................................................................................................................................ 81
PART 3: CASE STUDY 2 – OCRELIZUMAB (OCREVUS®) ........................................................................................................................................................... 84
THE CORE PRINCIPLES OF MIDD (THE "ABCs") ..................................................................................................................................................................... 88
GUIDELINES AND REGULATIONS IN CLINICAL RESEARCH......................................................................................................................................................... 89
THE NUREMBERG CODE (1947) ........................................................................................................................................................................................... 89
THE DECLARATION OF HELSINKI (1964) ............................................................................................................................................................................... 90
PART 4: ICH-GOOD CLINICAL PRACTICE (GCP) GUIDELINES (1997) ...................................................................................................................................... 91
THE EUROPEAN CLINICAL TRIAL DIRECTIVE (CTD, 2001) ...................................................................................................................................................... 92
THE BELGIAN LAW OF 7 MAY 2004 ....................................................................................................................................................................................... 92
DIFFERENCES BETWEEN SMALL MOLECULES AND BIOLOGICALS ............................................................................................................................................. 94
BIOLOGICALS – Definition ................................................................................................................................................................................................... 95
CLASSES OF BIOLOGICALS ................................................................................................................................................................................................. 95
ANTIBODIES ....................................................................................................................................................................................................................... 96
I. MODE OF ACTION – WHAT'S DIFFERENT IN THE ACTIVITY OF ANTIBODIES? .................................................................................................................. 97
II. PHARMACOKINETICS ................................................................................................................................................................................................. 99
III. SAFETY – WHAT'S DIFFERENT IN SAFETY OF BIOLOGICALS? ..................................................................................................................................... 101
IV. CLINICAL DEVELOPMENT – WHAT'S DIFFERENT? ..................................................................................................................................................... 102
VACCINE DEVELOPMENT ....................................................................................................................................................................................................... 106
WHAT IS A VACCINE? ........................................................................................................................................................................................................ 106
WHY DEVELOP VACCINES? .......................................................................................................................................................................................... 107
HOW VACCINES WORK................................................................................................................................................................................................ 107
TYPES OF VACCINES .................................................................................................................................................................................................... 107
Preclinical and Clinical Vaccine Development .................................................................................................................................................................... 110
PHARMACOVIGILANCE ................................................................................................................................................................................................ 111
OBSTACLES IN VACCINE DEVELOPMENT ........................................................................................................................................................................... 112
THERAPEUTIC VACCINES .................................................................................................................................................................................................. 113
IMPLEMENTATION AND RECOMMENDATIONS.................................................................................................................................................................... 113
PHARMACOVIGILANCE .......................................................................................................................................................................................................... 114
DEFINITIONS .................................................................................................................................................................................................................... 114
PRE-REGISTRATION / GCP REQUIREMENTS REGARDING PHARMACOVIGILANCE ............................................................................................................... 114
KEY DEFINITIONS FOR SAFETY REPORTING .................................................................................................................................................................. 115
CAUSALITY ASSESSMENT .................................................................................................................................................................................................. 116
Possible Consequences ............................................................................................................................................................................................... 117
GCP/LEGAL OBLIGATIONS FOR PHARMACOVIGILANCE IN CLINICAL TRIALS ...................................................................................................................... 117
PRE- AND POST-MARKETING ............................................................................................................................................................................................. 119
PHARMACEUTICAL MEDICINE: REGULATION CONCERNING MARKETING AUTHORIZATION (EU AND BELGIAN CONTEXT) ......................................................... 122
MARKET, PATIENT ACCESS, AND SOCIETAL PERSPECTIVE .................................................................................................................................................. 122
COMMON TECHNICAL DOCUMENT (CTD) ......................................................................................................................................................................... 126
ORPHAN MEDICINES ........................................................................................................................................................................................................ 127
CONDITIONAL MARKETING AUTHORIZATION (CMA) ..................................................................................................................................................... 128
MEDICINE PRICING AND REIMBURSEMENT ............................................................................................................................................................................ 131
HEALTH ECONOMIC INSTRUMENTS .................................................................................................................................................................................. 131
PRICING OF INNOVATIVE MEDICINES ................................................................................................................................................................................ 132
MANAGED ENTRY AGREEMENTS (MEAs) ............................................................................................................................................................................ 133
HEALTH SYSTEMS ................................................................................................................................................................................................................... 136
HEALTH SYSTEM ............................................................................................................................................................................................................... 136
WHO FRAMEWORK FOR HEALTH SYSTEM PERFORMANCE ASSESSMENT............................................................................................................................ 137
HISTORICAL EVOLUTION OF HEALTH SYSTEMS .................................................................................................................................................................. 138
TYPOLOGY AND CLASSIFICATION OF HEALTH SYSTEMS ..................................................................................................................................................... 140
DRUGS AND SOCIETY (PART I)................................................................................................................................................................................................. 143
FROM CHEMICAL COMPOUND TO TREATMENT.................................................................................................................................................................. 143
Drugs Can Be Used for Different Actions ....................................................................................................................................................................... 144
NOMENCLATURE OF DRUGS ............................................................................................................................................................................................. 144
REGISTERED DRUGS ON THE BELGIAN MARKET................................................................................................................................................................. 145
DANGER OF BRAND NAMES: SOUND-ALIKE AND LOOK-ALIKE (LASA) ............................................................................................................................ 146
INDICATIONS OF DRUGS................................................................................................................................................................................................... 146
UNIT DOSE PACKAGING AND IDENTIFICATION................................................................................................................................................................... 147
COLD CHAIN MANAGEMENT ............................................................................................................................................................................................. 147
QUALITY STANDARDS FOR DRUGS AND RAW MATERIALS ................................................................................................................................................... 147
PRESCRIPTION OF DRUGS ................................................................................................................................................................................................ 149
DRUG FORMULARY IN HOSPITALS ..................................................................................................................................................................................... 150
2
, DRUG DISTRIBUTION ........................................................................................................................................................................................................ 151
Information on Drugs......................................................................................................................................................................................................... 153
Drug Treatment – Compliance / Adherence......................................................................................................................................................................... 153
THE MEDICAL DEPARTMENT – AN INDUSTRY PERSPECTIVE ON MEDICINE DEVELOPMENT ....................................................................................................... 153
AI IN DRUG DEVELOPMENT ............................................................................................................................................................................................... 153
The Drug Development Funnel ........................................................................................................................................................................................... 154
GEOGRAPHY OF INNOVATION ........................................................................................................................................................................................... 155
Medical Department in Clinical Development..................................................................................................................................................................... 155
Regulatory Approval – A European Effort ....................................................................................................................................................................... 156
Health Technology Assessment (HTA) and Reimbursement – A National Effort ..................................................................................................................... 157
Commercialization – A Local Effort..................................................................................................................................................................................... 158
CLOSING REMARKS – THE DRUG LIFE CYCLE AND REWARD BOX ............................................................................................................................................. 158
First 2 lectures (Sofjia’s notes)
KEY TERMINOLOGY
• Generics: copies of small molecules that are chemically identical
• Biosimilars: copies of monoclonal antibodies (mAbs) that are chemically/structurally similar but not identical
• PRIME: Priority Medicines (EMA scheme for drugs with high unmet need)
• Orphan medicines: used for rare diseases
• ATMP: Advanced Therapy Medicinal Product (gene therapy, RNA-based therapies)
• BLA: Biologics License Application (US FDA)
• CTA: Clinical Trial Application (EU)
• CTIS: Clinical Trial Information System (EU portal for clinical trials)
• IND: Investigational New Drug (submitted between preclinical and clinical studies)
• NDA: New Drug Application (US FDA for marketing approval)
• MA(A): Marketing Authorisation (Application) (EU)
• CTD: Common Technical Document (standardized dossier for MA submission)
THREE WAVES OF DRUG DEVELOPMENT
1st Wave (1900s) - Small Molecules
• Symptomatic treatment; dose-dependent selectivity leads to off-target toxicity
• Example: statins target cholesterol synthesis enzyme; adverse effect = skeletal muscle toxicity
2nd Wave (1980s) - Biologicals
• Disease-modifying; target-driven effects → fewer off-target effects
• Example: PCSK9 inhibitors increase LDL-receptor recycling → lower LDL-cholesterol
3rd Wave (2000s) - ATMPs
• Potentially transformational; treat or modulate underlying cause
• Examples: gene therapy, siRNA, mRNA vaccines (e.g., SARS-CoV-2: synthetic mRNA → endogenous production of viral
antigen to induce immune response)
Trends
• Small molecules: decreasingly used
• Biologicals and ATMPs: increasingly used (mAbs, bispecific antibodies that bind two different antigens)
THE DRUG LIFE CYCLE
• Early period: drug discovery and development (preclinical animals + clinical humans) → high financial investment
• Middle period: drug marketed → return on investment
• Late period: loss of market exclusivity (patent expiry) → generics or biosimilars enter market
Approval Pathway
• FIH testing approval: CTA (EU) / IND (submitted between preclinical and clinical)
• Exploratory/early development: preclinical research + phase I/II
• Confirmatory/late development: phase III
• Marketing approval: NDA (US) or MA(A) (EU); CTD is the submission format
• Post-approval: reimbursement, commercialisation
3
, Quality and Ethical Standards
• Quality standards: GLP, GCP, GMP, GDP
• Ethical standards: Nuremberg Code, Declaration of Helsinki
• Regulations: CTR (Clinical Trial Regulation), MDR (Medical Device Regulation), IVDR (In Vitro Diagnostic Regulation)
DRUG DISCOVERY - OVERVIEW
Aim
• Identify pharmacologically active molecules that reach their target in sufficient amounts to produce therapeutic effect
without unacceptable toxicity
Strategic Requirements
• Identify unmet medical need and assess market opportunities and risks
Scientific Requirements
• Suitable disease models, targets, or screening strategies
Operational Requirements
• Sufficient staff, expertise, facilities, and financial resources
Drug Categories
• First-in-class: first drug on market with new mechanism of action
• Fast followers, best-in-class, me-too drugs
PHENOTYPIC VS. TARGET-BASED DRUG DISCOVERY
Phenotypic Drug Discovery (PDD)
• Compounds selected based on observable effects in cells or organisms without prior knowledge of molecular target
• Target-agnostic/unbiased
• Has produced many first-in-class medicines
• Can be done in vivo (ADME testing)
• Disadvantages: lower throughput; difficult to optimise drugs due to lack of initial knowledge about molecular MoA
• Empirical approach
Target-Based Drug Discovery (TDD)
• Dominant since 1990s; aims to identify and modulate specific molecular targets (proteins involved in disease
pathogenesis)
• Advances enabling TDD: RNA interference, high-throughput screening, mAbs, structure-based design (X-ray
crystallography, computational modelling)
• Hypothesis-driven
• Required assumptions: target relevant to human disease; target modulation produces desired effect; preclinical activity
translates to clinical benefit
• Risk: chosen target or MoA may not be sufficiently relevant to disease to provide therapeutic index → high attrition rates
• Structure-based drug design applied once target is known
Analysis of FDA-Approved NMEs (1999-2008)
• 259 NMEs approved; 75 first-in-class drugs
• Among first-in-class small molecule NMEs: more discovered via phenotypic screening than target-based approaches
(despite TDD dominance)
• Overall: 100 NMEs discovered via target-based approaches; biologics are inherently target-based
• Also: 164 follower drugs, 20 imaging agents
• Conclusion: over-reliance on target-based strategies (without sufficient attention to MoA and target relevance) can
reduce R&D productivity
ASSAYS IN ANTITUMORAL DRUG DISCOVERY
In Vitro Antiproliferation Assay (Phenotypic)
• Cancer cells seeded in 96-well plate; compounds added to identify growth inhibitors
• Cell viability measured by MTT assay: living cells convert MTT into dark purple product; dead cells do not
• Higher compound concentration = stronger growth inhibition
• Example: Stellettin identified as antitumoral compound (effective against lung cancer)
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