Early Drug Development : Strategies and Routes to First-in-Human Trials

The focus of early drug development has been the submission of an Investigational New Drug application to regulatory agencies. Early Drug Development: Strategies and Routes to First-in-Human Trials guides drug development organizations in preparing and submitting an Investigational New Drug (IND) application. By explaining the nuts and bolts of preclinical development activities and their interplay in effectively identifying successful clinical candidates, the book helps pharmaceutical scientists determine what types of discovery and preclinical research studies are needed in order to support a submission to regulatory agencies. EARLY DRUG DEVELOPMENT......Page 5 CONTENTS......Page 7 Contributors......Page 21 Foreword......Page 23 Preface......Page 25 PART I INTRODUCTION......Page 29 1.1.1 Pharmaceutical Research and Development Challenges......Page 31 1.1.2 Attrition During Discovery and Development......Page 33 1.1.3 Corporate Strategy Perspectives......Page 34 1.2.1 Target Identification......Page 36 1.2.2 Hit-to-Lead Identification......Page 37 1.2.3 Lead Optimization Strategies......Page 38 1.3.2 Pre-FIH Toxicology......Page 40 1.3.3 Formulation and Drug Delivery......Page 41 1.3.4 Pre-FIH Drug Metabolism and Pharmacokinetics......Page 42 1.4 The FIH Trial......Page 43 1.5 The Regulatory Landscape......Page 44 1.6 Contract Research Organizations......Page 46 1.7 Concluding Remarks on Introductory Perspectives......Page 50 References......Page 51 PART II LEAD OPTIMIZATION STRATEGIES......Page 53 2.1 Introduction......Page 55 2.2 Absorption......Page 58 2.2.1 Permeability......Page 60 2.2.2 Efflux Transport......Page 63 2.3.1 Plasma Protein Binding......Page 64 2.3.2 Brain Uptake......Page 68 2.3.3 Tissue Distribution......Page 69 2.4.1 In Vitro Metabolism Studies......Page 70 2.5 Excretion......Page 89 2.6 Pharmacokinetics......Page 92 2.7 Prioritizing ADME Screens......Page 96 2.8 In Silico ADME Screening......Page 97 2.9 The Promise of Metabolomics......Page 104 2.10 Conclusions......Page 106 References......Page 107 3.1 Introduction......Page 117 3.2 Prediction of Human Pharmacokinetic Behavior......Page 119 3.2.1 In Vitro Models for Predicting Intestinal Absorption, Intrinsic Hepatic Clearance, and Drug Interactions......Page 120 3.2.2 In Vivo Models for Predicting Pharmacokinetic Behavior......Page 135 3.3 Prediction of Drug Safety......Page 141 3.3.1 In Vitro Approaches for Predicting Drug Safety......Page 142 3.3.2 In Vivo and Ex Vivo Methods for Predicting Drug Safety......Page 144 3.3.3 In Silico Methods for Predicting Drug Safety......Page 147 3.4 Conclusions......Page 148 References......Page 149 4.1.1 Bioanalysis: The Primary Basis for Pharmacokinetic and Pharmacodynamic Evaluations......Page 159 4.1.2 Regulatory Initiatives in Bioanalysis......Page 160 4.2.1 Sample Preparation......Page 161 4.2.2 Component Separation......Page 167 4.2.3 Detection......Page 172 4.2.4 Ligand-Binding Assays......Page 177 4.2.5 Integration of Method Development Components: Example with LC-MS/MS......Page 182 4.3.1 Introduction to Validation......Page 184 4.3.2 The Primary Metrics: Acceptance Criteria......Page 185 4.3.3 Additional Validation Criteria......Page 193 4.4.3 Matrix Effects......Page 196 4.5 Partial and Cross-Validations......Page 197 4.6 Application of Validated Methods to Sample Analyses: Some Perspectives......Page 198 4.6.1 Stability......Page 199 4.6.4 Analytical Notes......Page 200 4.6.5 Acceptance Criteria......Page 201 4.6.6 Repeat Analyses of Incurred Samples......Page 202 4.6.7 Sample Stability and Incurred Samples......Page 204 4.6.8 Scientific Versus Production Issues......Page 205 4.6.9 Documentation......Page 206 4.6.10 Resources......Page 207 4.7 Risk-Based Paradigms: Discovery and Development Support......Page 216 4.7.1 Logistics and Discovery......Page 217 4.7.2 Early Involvement of Consultants and CROs......Page 220 4.7.3 Metabolites: Bioanalytical Issues Pre-FIH......Page 221 4.8 The Road to “First in Human”......Page 222 4.8.1 Clinical Collaboration Prior to Initiation of the FIH Trial......Page 223 4.9.1 European Union......Page 224 4.9.3 India......Page 225 4.10 Conclusions......Page 226 References......Page 227 PART III BRIDGING FROM DISCOVERY TO DEVELOPMENT......Page 233 5.1 Introduction......Page 235 5.2.1 Rationale for CMC Involvement in Discovery......Page 236 5.2.2 Pharmaceutical Properties......Page 237 5.2.3 CMC Interactions with Discovery at NCE Selection......Page 240 5.2.4 Biopharmaceuticals......Page 242 5.3.1 Solid-State Compounds......Page 244 5.3.2 Selection of Development Form (Crystalline State)......Page 245 5.3.3 Characterization of Drug Substance (Preformulation)......Page 248 5.4.1 Drug Synthesis and Formulation for Toxicity Studies: Meeting the Delivery Objectives......Page 250 5.4.2 Bridging to Formulations for FIH Studies......Page 252 5.5.1 Drug Substance Comparability with Material Used in Pre-FIH GLP Studies......Page 257 5.5.3 Analytical Development for Assay of Drug Substance and Drug Product......Page 258 5.5.4 Placebos and Blinding......Page 263 5.6.1 Interactions Across Disciplines......Page 264 5.6.2 Outsourcing (and Insourcing) CMC Work......Page 265 5.7.1 Indinavir......Page 266 5.7.2 Doxorubicin Peptide Conjugate......Page 269 5.8 Evolution of Drug Development: Implications for CMCs in the Future......Page 272 Resources......Page 273 References......Page 275 6.1 Introduction and Overview......Page 277 6.2 Timing of Safety Pharmacology Studies......Page 280 6.4.1 Study Designs......Page 282 6.5 Respiratory System Safety Pharmacology......Page 295 6.7 Gastrointestinal System Safety Pharmacology......Page 302 6.8 Autonomic Nervous System Safety Pharmacology......Page 303 6.9 Other Systems......Page 304 6.10 Discussion and Conclusions......Page 305 References......Page 307 PART IV PRE-IND DRUG DEVELOPMENT......Page 309 7.1 Introduction......Page 311 7.2 Toxicology Support of Discovery......Page 312 7.3 Goals of the Pre-FIH Toxicology Program......Page 313 7.6.1 Availability Issues......Page 314 7.6.2 Impurity Considerations......Page 315 7.7.1 Comparative In Vitro Metabolism......Page 316 7.7.2 Genetic Toxicology......Page 317 7.8.2 Validated Analytical Assays for Dosing Solutions or Suspensions......Page 318 7.9.1 Timing of the IND/CTA......Page 319 7.9.3 Pilot In Vivo Studies for Dose Selection and Bleeding Time Determinations......Page 320 7.10 GLP Toxicology Program......Page 321 7.10.1 Toxicology Requirements for Initiating an FIH Trial......Page 322 7.10.2 Toxicology Protocols......Page 323 7.10.3 Study Monitoring......Page 330 7.10.5 Considerations of the NOAEL and MTD in Protocol Design......Page 331 7.11 Pre-IND Meeting......Page 332 7.12 Conclusions......Page 333 References......Page 334 8.1 Introduction......Page 337 8.2 Historical Perspectives......Page 338 8.3 Regulatory Considerations......Page 339 8.4.1 Drug Supply Requirements......Page 340 8.4.2 Species Selection......Page 341 8.4.4 Dose-Related Exposure......Page 342 8.4.5 Changes in Pharmacokinetics Following Multiple Dosing......Page 343 8.4.7 Bioanalytical Method......Page 344 8.4.8 Evaluation of Metabolites......Page 345 8.4.10 Matrix Considerations......Page 349 8.4.12 Gender......Page 350 8.4.13 Dose Selection......Page 351 8.4.15 Blood Sampling Variables......Page 352 8.4.16 Sampling Times......Page 357 8.4.17 Considerations with Biopharmaceutics......Page 359 8.5.1 Data Analysis (Noncompartmental Versus Compartmental)......Page 360 8.5.2 Noncompartmental Kinetic Parameters......Page 361 8.5.4 Physiologically Based Toxicokinetic Modeling......Page 366 8.6.3 Confirmation of Exposure and Evaluation of Dose Proportionality......Page 367 8.6.4 Exposure after Single and Multiple Dosing: Accumulation Perspectives......Page 369 8.6.5 Gender Effects......Page 371 8.6.6 Relationship to Toxicology Findings......Page 372 8.7 Role of Toxicokinetics in Different Types of Toxicity Studies......Page 373 8.7.2 Dose-Range-Finding and Tolerability Studies......Page 374 8.7.5 Safety Pharmacology and Specialty Studies......Page 375 8.7.7 Reproductive Toxicology......Page 376 8.7.8 Carcinogenicity Studies......Page 377 8.8.1 Safety Margins: Role in Setting Clinical Doses for FIH Studies......Page 378 8.8.2 Role of Protein Binding and Blood Partitioning......Page 380 8.8.3 Toxicokinetics: Caution about Safety Margins......Page 381 8.8.4 Safety Margins for Different Toxicity Profiles......Page 382 References......Page 383 9.1 Introduction......Page 389 9.2 Hazard and Risk......Page 391 9.3 U.S. GLP Regulations......Page 394 9.3.1 Subpart A: General Provisions......Page 395 9.3.2 Subpart B: Organization and Personnel......Page 397 9.3.4 Subpart D: Equipment......Page 404 9.3.5 Subpart E: Testing Facilities Operation......Page 405 9.3.6 Subpart F: Test and Control Articles......Page 406 9.3.7 Subpart G: Protocol for and Conduct of a Nonclinical Laboratory Study......Page 407 9.3.8 Subpart J: Reports and Records......Page 412 9.4 GLPs in the Bioanalytical Laboratory......Page 415 9.4.2 Equipment and Testing Facilities Operation......Page 417 9.4.3 Some Challenges in the Bioanalytical Laboratory......Page 419 9.5 Moving Into the Future: A Closing Overview......Page 421 Appendix 9.1: Preambles—Perspectives on GLP Requirements......Page 423 Appendix 9.2: International Regulations......Page 424 Appendix 9.3: Paraphrased FDA GLP Definitions......Page 426 Appendix 9.4: FDA Inspections......Page 427 Appendix 9.5: Critical Phase Inspections—What, Why, How, and When?......Page 429 Appendix 9.7: 21 CFR Part 11......Page 430 Appendix 9.8: SOP Generation and Review......Page 436 Appendix 9.9: Study Director’s Responsibilities......Page 439 Appendix 9.10: Regulatory Requirements for the Study Protocol......Page 441 References......Page 444 PART V PLANNING THE FIRST-IN-HUMAN STUDY AND REGULATORY SUBMISSION......Page 449 10.1 Introduction......Page 451 10.2 Characteristics of Well-Behaved Therapeutic Candidates......Page 452 10.3 Regulatory Guidances for FIH-Enabling Nonclinical Safety Assessment: General Principles......Page 454 10.5 Establishing the First-in-Human Dose......Page 455 10.5.1 Phase I Clinical Trial Support: Use of the NOAEL-Based Approach......Page 456 10.5.2 Estimating a Human Dose......Page 460 10.6 Phase I Clinical Trial Support: Use of the MABEL or Pharmacologically Active Dose......Page 467 10.6.1 Predicting the MABEL and PAD in Humans......Page 469 10.7 Support of Exploratory Clinical Studies......Page 473 10.8.1 Toxicological Considerations......Page 474 10.8.2 Differences Between Animals and Humans That May Modify Exposure or Response......Page 475 10.9.1 Chemistry, Manufacturing, and Control......Page 476 10.9.3 Clinical......Page 477 10.11 Concluding Perspective......Page 478 10.12 Four Case Studies......Page 479 References......Page 487 11.1 Introduction......Page 493 11.2.2 European Position Paper on Microdose Clinical Trials......Page 495 11.2.3 FDA Critical Path Initiative......Page 496 11.2.4 FDA Guidance on Exploratory IND Studies......Page 497 11.2.5 Belgium National Guidance on Exploratory Trials......Page 500 11.2.6 The ExpIND (or ExpCTA) Submission......Page 501 11.3 Experience and Various Perspectives on ExpINDs or ExpCTAs......Page 502 11.3.1 Microdose Studies......Page 503 11.3.2 Pharmacological Dose and MOA Studies......Page 507 11.4 Some Reactions and Perspectives on the ExpIND/ExpCTA Initiative......Page 508 11.4.2 What an ExpIND/ExpCTA Cannot Do......Page 509 11.4.3 Some Potential Drawbacks or Challenges in the Conduct of an ExpIND/ExpCTA Program......Page 510 11.6 Conclusions......Page 512 References......Page 514 12.1 Introduction and Background......Page 517 12.2 Selection of the Molecule: Contrasts to Small-Molecule Considerations......Page 518 12.2.2 In Vitro Activity Profiling, Sequence Homology, and the Use of Homologous Molecules for Nonclinical Efficacy and Safety Assessments......Page 519 12.2.3 In Vivo Profiling of Biopharmaceutical Activity......Page 520 12.3 Production and Process Considerations in Pre-FIH Development......Page 521 12.4 Bioanalytical Assay Considerations......Page 523 12.5.1 ICH S6 Guideline......Page 524 12.5.2 Considerations and Typical Program Designs for Nonclinical Safety Assessment of Biopharmaceutics......Page 525 12.6.1 Changes in Production and Process, and Impact on Completed Studies......Page 535 12.7 The TeGenero Incident and Implications for Biopharmaceutic Nonclinical Safety Evaluation Programs......Page 536 12.8 Conclusions......Page 537 References......Page 538 13.1 Introduction: Initiate Product Development with the End in Mind......Page 541 13.2 Importance of Project Management......Page 544 13.3 FDA Input Early and Often......Page 546 13.4 IND Submission in the United States......Page 547 13.5 Global Clinical Trials......Page 549 13.6.1 Europe......Page 551 13.6.2 Canada......Page 554 13.6.3 Australia......Page 556 13.6.4 Latin America......Page 558 13.6.5 China......Page 562 13.6.6 India......Page 563 13.6.7 Japan......Page 565 References......Page 567 14.1 Introduction......Page 571 14.2 Submission Strategies......Page 572 14.2.1 Regulatory Environment......Page 573 14.2.2 Clinical Considerations......Page 574 14.3.2 General Considerations for Dossier Preparations......Page 577 14.3.3 Coordination of the Disciplines......Page 581 14.3.4 Document Preparation......Page 585 14.4.1 Regulatory Perspective......Page 587 14.4.2 Chemistry, Manufacturing, and Controls......Page 593 14.4.3 Nonclinical Sections......Page 602 14.4.4 Clinical Components......Page 608 14.5.1 Regulatory Perspective......Page 611 14.5.2 Quality......Page 614 14.5.3 Nonclinical Sections......Page 615 14.6.3 Nonclinical Sections......Page 616 14.8 Biopharmaceuticals......Page 617 14.9.1 Gap Analysis......Page 619 14.9.2 Preparation for Regulatory Queries......Page 620 Appendix 1: Abbreviations and Acronyms......Page 623 Appendix 2: Definitions and Glossary of Terms......Page 629 Appendix 3: Some Relevant Government and Regulatory Documents......Page 635 Appendix 4: Some Relevant Resources with Web Sites......Page 641 Index......Page 645 Drug discovery and early drug development / Mitchell N. Cayen ADME strategies in lead optimization / Amin A. Nomeir Prediction of pharmacokinetics and drug safety in humans / Peter L. Bullock Bioanalytical strategies / Christopher Kemper Chemistry, manufacturing and controls : the drug substance and formulated drug product / Orn Almarsson and Christopher J. Galli Preclinical safety pharmacology studies recommended for supporting first-in-human (FIH) clinical trials / Duane B. Lakings Toxicology program to support initiation of a clinical phase I program for a new medicine / Hugh E. Black, Stephen B. Montgomery, and Ronald W. Moch Toxicokinetics in support of drug development / Gary Eichenbaum, Vangala Subrahmanyam, and Alfred Tonelli Good laboratory practices / Anthony B. Jones, Kathryn Hackett-Fields, and Shari L. Perlstein Estimation of starting dose for phase I clinical programs / Lorrene A. Buckley ... [et al.] Exploratory INDS/CTAS / Mitchell N. Cayen Unique considerations for biopharmaceutics / Laura P. Andrews and James D. Green Project management and international regulatory requirements for first-in-human trials / Carolyn D. Finkle and Judith Atkins First-in-human regulatory submissions / Mary Sommer ... [et al.]. Drug development is a highly resource intensive effort. The high attrition rate during nonclinical and especially clinical evaluation demands that the candidate drug selection process he as cost and time effective as possible. Focusing on the critical early stages of drug development, this book guides investigators through the continuum of disciplines that play a role in determining whether a new chemical entity with demonstrated pharmacological activity should progress to clinical evaluation in human subjects. Moreover, it will help them prepare and submit an Investigational New Drug (IND) application