Basics and Clinical Applications of Drug Disposition in Special Populations

About the Editors xxi List of Contributors xxiii Foreword xxix Preface xxxi 1 Pharmacokinetic Principles and Concepts: An Overview 1 Seth K. Amponsah and Yahwant V. Pathak 1.1 Introduction 1 1.2 Pharmacokinetic Parameters 2 1.2.1 Absorption 2 1.2.2 Distribution 3 1.2.3 Metabolism 4 1.2.4 Excretion 5 1.3 Pharmacokinetic Models 5 1.4 Applications 6 1.5 Conclusion 7 References 7 2 Model-Based Pharmacokinetic Approaches 11 Manish P. Patel, Kashyap M. Patel, Shakil Z. Vhora, Anuradha K. Gajjar, Jayvadan K. Patel, and Amitkumar K. Patel 2.1 Introduction 11 2.1.1 Importance of PK 12 2.1.2 Overview of Model-Based Approaches 13 2.2 Basics of Pharmacokinetics 14 2.2.1 Key Pharmacokinetic Parameters 14 2.2.1.1 Absorption 14 2.2.1.2 Key Parameter 14 2.2.1.3 Distribution 14 2.2.1.4 Key Parameter 15 2.2.1.5 Metabolism 15 2.2.1.6 Key Parameter 15 2.2.1.7 Excretion 15 2.2.1.8 Key Parameter 15 2.2.2 Differences Between Traditional and Model-Based Pharmacokinetic Approaches 16 2.3 Pharmacokinetic (PK) Models 17 2.3.1 Introduction 17 2.3.2 Compartment Modeling 18 2.3.2.1 One-Compartment Model 21 2.3.2.2 Multi-Compartment Model 21 2.3.2.3 Two-Compartment Model 24 2.3.3 Population PK Model 25 2.3.4 Physiologically Based PK (PBPK) Model 26 2.4 Model Development and Validation 27 2.4.1 Data Requirements for Model Development 27 2.4.2 Data Requirements for Model Validation 29 2.4.3 Steps in Model Building (E.g., Model Selection and Parameter Estimation) 29 2.5 Applications of Model-Based Approaches 31 2.5.1 Dose Optimization 31 2.5.2 Predicting Drug Interactions 32 2.5.3 Drug Tailoring in Special Populations (E.g., Pediatrics, Geriatrics, and Renal Impairment) 33 2.5.4 Translational PK from Preclinical to Clinical Settings 34 2.6 Modeling in Special Populations 36 2.6.1 Challenges and Considerations 36 2.6.1.1 Challenges in PK Modeling 36 2.6.1.2 Considerations in PK Modeling 36 2.7 Software and Tools for PK Modeling 37 2.7.1 Gastroplus™ 38 2.7.2 Berkeley Madonna 38 2.7.3 MATLAB 38 2.7.4 PK-Sim® 39 2.7.5 Simcyp® 39 2.7.6 Auxiliary PBPK Modeling Software 39 2.7.6.1 Julia 39 2.7.6.2 Nonmem 39 2.7.6.3 Phoenix WinNonlin 40 2.7.6.4 GraphPad Prism 40 2.7.6.5 Minitab 40 2.7.6.6 PlotDigitizer 40 2.7.6.7 GNU MCSim 40 2.7.6.8 WebPlotDigitizer 40 2.8 Regulatory Perspectives of PK Modeling 40 2.9 Future Directions of PK Modeling 43 2.10 Conclusion 43 Abbreviations 44 References 45 3 Physiologically Based Pharmacokinetic Modeling 53 Mahesh P. More and Rahul S. Tade 3.1 Introduction 53 3.2 Significance of PBPK Modeling 56 3.3 Principles for the Development of PBPK for Special Populations 57 3.4 Data Integration for Special Populations 57 3.4.1 Demographic Data 58 3.4.2 Physiological Consideration 58 3.4.3 Ontogeny 58 3.4.4 Age and Maturation Changes 59 3.4.5 Steady State Volume of Distribution (Vdss) 59 3.5 Applications of PBPK Modeling 60 3.5.1 Dose Optimization/Regimen/Selection 60 3.5.2 Dose Individualization/Precision Dosing 61 3.5.3 Biopharmaceutics 62 3.6 Regulatory Applications/Pre–Post Market Utilization 62 3.7 Case Studies 64 3.7.1 Simulation Application 64 3.7.2 Successful Applications 67 3.8 Lessons Learned 68 3.9 Conclusion 68 References 70 4 Therapeutic Drug Monitoring in Special Populations 75 James A. Akingbasote, Sandra K. Szlapinski, Elora Hilmas, Kyle Weston, Yelena Wu, and Alexandra Burton 4.1 Introduction 75 4.2 Pediatrics 76 4.2.1 Importance of TDM in Pediatrics 76 4.2.2 Pharmacokinetic Differences in Pediatric Patients 77 4.2.3 Drug Absorption in the Pediatric Population 77 4.2.4 Drug Distribution in the Pediatric Population 78 4.2.5 Drug Metabolism and Elimination in the Pediatric Population 79 4.3 TDM Practices in Pediatrics 79 4.3.1 Vancomycin 80 4.3.2 Aminoglycosides 81 4.3.3 Ganciclovir/Valganciclovir 82 4.3.4 Antiepileptic Drugs (AEDs) 83 4.3.5 Enoxaparin 84 4.4 Conclusion 85 4.5 Pregnancy 85 4.5.1 Physiological Adaptations in Pregnancy 85 4.5.2 Current State of Clinical Practice of TDM in Pregnancy 87 4.5.3 TDM in Pregnancy 89 4.5.3.1 Antiepileptics 89 4.5.3.2 Antidepressants 90 4.5.3.3 Antiretroviral Drugs 91 4.5.3.4 Immunomodulatory Drugs 93 4.5.4 Challenges in the Implementation of TDM in the Pregnant Population 94 4.6 The Elderly 95 4.6.1 Physiological Changes in the Elderly 95 4.6.2 Effect of Aging on Drug Pharmacokinetics 95 4.6.3 Application of TDM in the Elderly 97 4.6.3.1 Cardiac Glycosides 98 4.6.3.2 Serotonin–Norepinephrine Reuptake Inhibitor (SNRI) 98 4.6.3.3 Anticoagulants 99 4.6.3.4 Benzodiazepines 99 4.7 Conclusion 101 4.8 Hepatic and Renal Impairments 101 4.8.1 Hepatic Impairment 102 4.8.2 TDM in Patients with Hepatic Impairment 104 4.8.2.1 Meropenem 105 4.8.2.2 Metoprolol 105 4.8.2.3 Midazolam 106 4.8.3 Renal Impairment 107 4.8.4 Prerenal Disease 109 4.8.5 Intrinsic Renal Vascular Disease 109 4.8.6 Intrinsic Glomerular Disease (Nephritic or Nephrotic) 109 4.8.7 TDM in Renal Impairment 109 4.8.7.1 Vancomycin 111 4.8.7.2 Metformin 111 4.9 Conclusion 112 4.10 Overall Conclusion and Future Direction 112 Acknowledgment 113 References 114 5 Optimization of Drug Dosing Regimen 133 Vivek Patel, Kartik Hariharan, Dhruv Shah, Arindam Halder, Ajay J. Khopade, Amitkumar K. Patel, and Jayvadan K. Patel 5.1 Introduction 133 5.2 Dosing Regimen Optimization Approaches and Strategies 134 5.2.1 Models Used for Dosing Regimen Selection 134 5.2.1.1 Pharmacometric Models 134 5.2.1.2 PK Models 135 5.2.1.3 Empirical Dose–Response Models 136 5.2.1.4 Multiple Comparison Procedures Models (MCP-Mod) 136 5.2.1.5 Model Averaging 137 5.2.2 Role of Patient Characteristics in Dose Selection 137 5.2.2.1 Phenotype-Guided Dosing 137 5.2.2.2 Genotype-Guided Drug Dosing 138 5.2.3 Therapeutic Drug Monitoring (TDM) 138 5.3 Dosing Regimen in Special Populations 139 5.3.1 Dosing Regimen in Cancer Patients 139 5.3.1.1 Metronomic Chemotherapy 140 5.3.2 Dosing Regimen for Patients on Antimicrobial Therapy 142 5.3.2.1 Antimicrobial Stewardship Strategy 145 5.3.2.2 Mathematical Models for Optimizing Antimicrobial Therapy 146 5.3.2.3 Antimicrobial Dosing Strategies During CRRT 147 5.3.2.4 Methods for Enhancing Dosing of Antimicrobials via Nebulization 149 5.3.3 Dosing Regimen in Pediatric Patients 149 5.3.3.1 Physiological Differences Between Pediatric and Adult Patients 149 5.3.3.2 Application of MIDD in Pediatric Dose Selection 149 5.3.3.3 Scaling from Adults to Pediatric Patients 150 5.3.3.4 Scaling from Animals to Pediatric Patients 150 5.3.3.5 Integrating Mechanistic Models in Neonates and Infants 150 5.3.3.6 Dose Optimization in Neonates and Infants 151 5.4 Conclusion 151 References 152 6 Artificial Intelligence in Drug Development 161 Surovi Saikia, Aparna Anandan, Unais Annenkottil, Vishnu P. Athilingam, Partha P. Kalita, and Viswanadha V. Padma 6.1 Introduction 161 6.2 Application of AI in Drug Design 162 6.2.1 Target Identification and Validation 162 6.2.2 Drug Candidate Design and Optimization 162 6.2.3 Virtual Screening and Molecular Docking 163 6.2.4 Synthesis Planning 163 6.2.5 Predicting Drug Toxicity and Pharmacokinetics 163 6.2.6 Personalized Medicine 163 6.3 AI Use in Drug Formulation 163 6.4 Drug Release Characterization Using AI 164 6.5 AI-Based Dose/Dosing Regimen 165 6.6 Dissolution Rate Predictions with AI 166 6.7 Clinical End-Point Evaluation with AI 166 6.8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes 167 6.9 AI-Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring 169 6.10 AI-Based Tools for Metabolism and Clearance Prediction 169 6.11 Limitations of Existing Tools 171 6.12 Conclusions 171 6.13 Conflict of Interest 171 Acknowledgments 171 References 172 7 Drug Disposition in Neonates and Infants 179 David Gyamfi, Emmanuel B. Amoafo, Awo A. Kwapong, Mansa Fredua-Agyeman, and Seth K. Amponsah 7.1 Introduction 179 7.2 Drug Absorption in Neonates and Infants 180 7.3 Drug Distribution in Neonates and Infants 182 7.4 Hepatic Metabolism of Drugs in Neonates and Infants 185 7.4.1 Phase I Metabolism 185 7.4.2 Phase II Metabolism 187 7.5 Drug Excretion in Neonates and Infants 188 7.6 Pharmacodynamics in Neonates and Infants 190 7.7 Age-Related Dosing Regimen in Neonates and Infants 190 7.8 Conclusion 192 References 193 8 Drug Disposition in Adolescents 203 Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Pallab Pramanik 8.1 Introduction 203 8.2 Physiological Considerations in Adolescents 206 8.2.1 Organ Development: Liver and Kidney Maturation 206 8.2.2 Variations in Body Composition 208 8.2.3 Hormonal Changes 208 8.2.3.1 Males 208 8.2.3.2 Females 209 8.2.4 Other Physiological Changes 210 8.3 Medication Adherence Challenges in Adolescents 211 8.4 Psychological Development on Drug Disposition 212 8.5 Risk-Taking behaviors and Their Implications on Medication Use 213 8.6 Drug Use Among Adolescents 215 8.6.1 Acetaminophen Use in Adolescents 215 8.6.2 Antidepressant Use in Adolescents 215 8.6.3 Drugs for ADHD 216 8.7 Pharmacokinetic Variability in Adolescents Drug Examples 217 8.7.1 Acetaminophen 217 8.7.2 Theophylline 217 8.7.3 Antidepressants 218 8.7.4 Drugs for ADHD 218 8.8 Legal and Ethical Considerations 219 8.8.1 Consent and Confidentiality in Adolescent Healthcare 219 8.8.2 Involving Adolescents in Treatment Decisions 220 8.8.3 Regulatory Aspects of Adolescents Drug Prescribing 221 8.9 Conclusion 221 References 222 9 Drug Disposition in Pregnancy 229 Jacob Treanor, Stefanos Belavilas, Dominique Cook, Justin Cole, Amruta Potdar, and Charles Preuss 9.1 Introduction 229 9.2 Physiological Changes in Pregnancy 230 9.2.1 Changes in Absorption 231 9.2.2 Changes in Distribution and Free Medication 231 9.2.3 Changes in Cytochrome Metabolism 233 9.2.4 Changes in Renal Excretion 233 9.2.5 General Considerations in Drug Dosing with Pregnancy 234 9.3 Placental Drug Disposition 234 9.3.1 Placental Barrier Anatomy and Physiology 235 9.3.2 Placental Transport Mechanisms 237 9.3.3 Methods of Study for Placental Drug Transfer 238 9.4 Drug Classification in Pregnancy 239 9.5 Pharmacokinetic (PK) Modeling 241 9.6 Physiologically Based Pharmacokinetic (PBPK) Modeling 242 9.7 Limitations in PK and PBPK Models 244 9.8 PBPK Model Variables 244 9.9 Determining Treatment During Pregnancy 245 9.10 Fetal Blood Flow and Drug Processing 245 9.10.1 Hepatic and Renal Processing 246 9.10.2 Embryonic Staging 248 9.11 Teratogens 249 9.11.1 Thalidomide 250 9.11.2 Alcohol 251 9.11.3 Smoking and E-cigarettes 251 9.11.4 Caffeine 252 9.11.5 Antibiotics 253 9.11.6 Retinoids 254 9.12 Conclusion 257 Abbreviations 257 References 258 10 Drug Disposition in Obesity 265 Seema Kohli and Ankita A. Singh 10.1 Introduction 265 10.2 Index of Obesity 265 10.3 Pathogenesis of Obesity/Overweight 266 10.4 Drug Disposition in Obesity 267 10.4.1 Absorption 267 10.4.2 Distribution 268 10.4.3 Metabolism 268 10.4.4 Renal Excretion 270 10.5 Drug Dose Calculations in Obese Patients 270 10.5.1 Volume of Distribution (Vd) 270 10.5.2 Drug Clearance 271 10.5.3 Body Size Description 271 10.5.4 Drug Dose Calculation 272 10.6 Disposition of Drugs in Obesity 273 10.6.1 Volatile Agents 273 10.6.2 Thiopental 274 10.6.3 Propofol 274 10.6.4 Midazolam 274 10.6.5 Acetaminophen 274 10.6.6 Opioids 275 10.6.7 Unfractionated Heparin 275 10.6.8 Cephazolin 275 10.6.9 Enoxaparin 275 10.7 Conclusion 276 References 276 11 Drug Disposition in Critical Care Patients 281 Chinenye E. Muolokwu, Benjamin Tagoe, Michael M. Attah, and Seth K. Amponsah 11.1 Introduction 281 11.2 Pharmacokinetic Considerations in Critical Care Patients 282 11.2.1 Drug Absorption Considerations in Critical Care Patients 282 11.2.2 Drug Distribution Considerations in Critical Care Patients 283 11.2.3 Drug Metabolism Considerations in Critical Care Patients 284 11.2.4 Drug Excretion Considerations in Critical Care Patients 285 11.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients 286 11.3.1 Antibacterial and Antifungal Agents 286 11.3.1.1 Aminoglycosides 287 11.3.1.2 β-Lactam Antibiotics 288 11.3.1.3 Fluoroquinolones 288 11.3.1.4 Oxazolidinones 289 11.3.1.5 Antifungal Agents 289 11.3.2 Inotropes 291 11.3.3 Antiviral Drugs 292 11.3.4 Narcotic Analgesics 292 11.3.4.1 Morphine and Pethidine 292 11.3.4.2 Fentanyl and Derivatives 293 11.3.5 Sedatives and Hypnotics 293 11.3.5.1 Midazolam 294 11.3.5.2 Lorazepam 295 11.3.6 Neuromuscular Blockers 295 11.4 Conclusion 297 References 297 12 Drug Disposition in Renal Insufficiency 305 Sarah Nestler, Deborah Liaw, Gabriella Blanco, Rana Hanna, Ellen Si, and Charles Preuss 12.1 Renal Physiology 305 12.1.1 General Anatomical Structure 305 12.1.2 General Function of the Nephron 306 12.1.3 Water Regulation 306 12.1.4 Glomerular Filtration Rate (GFR) 307 12.1.5 Acid–Base Regulation 307 12.2 Glomerular Filtration Rate 307 12.3 Acute Kidney Injury 308 12.3.1 Diagnostic Criteria and Classification 308 12.3.2 Causes of AKI 310 12.3.3 Prerenal 310 12.3.4 Intrinsic 310 12.3.5 Postrenal 311 12.4 Chronic Kidney Disease 311 12.4.1 Diagnostic Criteria and Classification 311 12.4.2 Causes of Chronic Kidney Disease 312 12.5 Medication Dosing Modifications 313 12.5.1 Medication Dosing in Patients with CKD 313 12.5.2 Medications to Treat CKD-Induced HTN and Medications to Avoid in CKD 314 12.5.2.1 Antihypertensives 314 12.5.2.2 Hypoglycemics 316 12.5.2.3 Antimicrobials 317 12.5.2.4 Statins 321 12.5.2.5 NSAIDs 322 12.5.2.6 Analgesics 322 12.6 Epidemiology and Outcomes of Patients with CKD 323 References 324 13 Drug Disposition in Hepatic Insufficiency 327 Fried A. Abilba, Jacob A. Ayembilla, and Raphael N. Alolga 13.1 Introduction 327 13.2 The Spectrum of Liver Diseases 328 13.3 Liver Function and Drug Metabolism 330 13.3.1 Impact of Hepatic Insufficiency on Drug Metabolism 331 13.3.2 Pharmacokinetic Changes in Hepatic Insufficiency 332 13.3.3 Effect of Liver Diseases on Pharmacokinetics of Drugs 333 13.4 Dosing Algorithms in Clinical Practice 334 13.4.1 Drug Selection 335 13.4.2 Dosing Adjustments 336 13.4.3 Pharmacokinetic Considerations 336 13.5 Drug Disposition and Factors That Influence Drug Disposition 336 13.6 Major Classes of Drugs and Hepatic Insufficiency 337 13.6.1 Anticoagulants 337 13.6.2 Antibiotics 338 13.6.3 Analgesics 338 13.6.4 Anticonvulsants 338 13.6.5 Antidepressants 339 13.6.6 Antiretrovirals 339 13.7 Cases Demonstrating Application of Dosing Algorithms 339 13.7.1 Case 1: Warfarin for Anticoagulation 339 13.7.1.1 The Use of Warfarin in a Patient with Hereditary Bleeding Disorder 339 13.7.1.2 Dosing Algorithm of Warfarin 340 13.7.2 Case 2: Acetaminophen for Pain Management 340 13.7.2.1 Dosing Algorithm for Paracetamol and Other Cytochrome p 450 Enzyme-inducing Drugs in Hepatic Insufficiency Using Child-Pugh Score 341 13.7.3 Case 3: Valproic Acid for Seizure Control 341 13.7.4 Case 4: Metronidazole for Infection 342 13.7.5 Case 5: Efavirenz for HIV Treatment 342 13.8 Limitations of Current Dosing Strategies 342 13.9 Conclusion and Future Perspectives 343 13.9.1 Emerging Technologies and Precision Medicine 343 13.9.2 Potential Impact of Pharmacogenomics 344 13.9.3 Areas of Research Interest 344 References 345 14 Drug Disposition in Geriatrics 349 Ali Karimi, Samuel Cockey, Millena Levin, Teresa Travnicek, Nishanth Chalasani, and Charles Preuss 14.1 Introduction 349 14.2 Absorption 351 14.3 Distribution 352 14.4 Metabolism 354 14.5 Excretion 356 14.6 Hepatic 360 14.7 Renal 361 14.8 Cardiac 363 14.9 Sex Differences 363 14.10 Psychoactive Drugs 365 14.11 Anesthesiology Drugs 366 14.12 Drug Interactions 367 14.13 Drug Side Effects 368 14.14 Conclusion 371 Abbreviations 372 References 373 15 Considerations and Regulatory Affairs for Clinical Research in Special Populations 377 Stephanie Leigh, Maxine Turner, and Goonaseelan C. Pillai 15.1 Introduction 377 15.2 Regulatory Frameworks for Clinical Research in Special Populations 378 15.2.1 The Historical Evolution of Regulatory Frameworks for Special Population Research 378 15.2.2 Current Global Regulatory Frameworks for Special Population Research 380 15.2.3 Current Regional Regulations Concerning Clinical Research Involving Special Populations 382 15.2.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 382 15.2.3.2 Europe: European Medicines Agency (EMA) 383 15.2.3.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 383 15.2.3.4 Australia: The Therapeutic Goods Administration (TGA) 384 15.2.3.5 Brazil: National Health Surveillance Agency (ANVISA) 385 15.2.3.6 India: Central Drugs Standard Control Organization (CDSCO) 387 15.2.3.7 China: National Medical Products Administration (NMPA) 388 15.2.3.8 South Africa: The South African Health Products Regulatory Authority (SAHPRA) 389 15.2.4 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Special Populations 391 15.3 Key Considerations for Clinical Trials in Special Population Groups 392 15.3.1 Pediatric Population Groups 392 15.3.1.1 Regulatory Guidelines Governing Pediatric Clinical Research 392 15.3.2 Regional Legislations Governing Clinical Research in Pediatric Populations 393 15.3.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 393 15.3.2.2 Europe: European Medicines Agency (EMA) 395 15.3.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 396 15.3.2.4 India: Central Drugs Standard Control Organization (CDSCO) 396 15.3.2.5 Other Global Jurisdictions 397 15.3.3 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Pediatric Populations 398 15.3.4 Ethical Considerations for Clinical Research in Pediatric Populations 398 15.3.4.1 Assent and Informed Consent 399 15.3.4.2 Participant Recruitment 402 15.4 Pregnant Population Groups 403 15.4.1 Historical Exclusion of Pregnant Persons in Clinical Research 403 15.4.2 Regulatory Guidelines Governing Clinical Research in Pregnant Persons 404 15.4.3 Regional Legislations Governing Clinical Research in Pregnant Persons 406 15.4.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 406 15.4.3.2 Europe: European Medicines Agency (EMA) 406 15.4.3.3 Australia: The Therapeutic Goods Administration (TGA) 407 15.4.3.4 Brazil: National Health Surveillance Agency (ANVISA) 407 15.4.3.5 India: Central Drugs Standard Control Organization (CDSCO) 408 15.4.3.6 China: National Medical Products Administration (NMPA) 409 15.4.4 Challenges and Barriers to Clinical Research in Pregnant Persons 409 15.5 Geriatric Populations 410 15.5.1 Key Regulatory Guidelines Governing Geriatric Clinical Research 411 15.5.2 Regional Legislations Governing Clinical Research in Geriatric Populations 412 15.5.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 412 15.5.2.2 Europe: European Medicines Agency (EMA) 414 15.5.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 415 15.5.2.4 India: Central Drugs Standard Control Organization (CDSCO) 416 15.5.2.5 Other Global Jurisdictions 417 15.5.3 Challenges and Barriers to Clinical Research in Geriatric Populations 417 15.6 Critical Care 417 15.6.1 Key Regulatory Guidelines Governing Critical Care Clinical Research 418 15.6.2 Regional Legislations Governing Clinical Research in Critical Care Populations 418 15.6.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 418 15.6.2.2 Europe: European Medicines Agency (EMA) 420 15.6.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 420 15.6.2.4 India: Central Drugs Standard Control Organization (CDSCO) 421 15.6.2.5 Other Global Jurisdictions 421 15.6.3 Challenges and Barriers to Clinical Research in Critical Care Populations 422 15.7 Summary Points 422 15.7.1 Regulatory Guidelines 422 15.7.2 Ethical Considerations 423 15.7.3 Participant Recruitment 423 15.8 Conclusion 423 References 424 Index 435