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

Description

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.

Table of Contents

Foreward.
Preface.
List of Contributors.

Part I: Introduction.

1 Drug Discovery and Early Drug Development (Mitchell N. Cayen).

• 1.1 The Drug Discovery and Development Scene.
• 1.2 Drug Discovery.
• 1.3 Pre-FIH Drug Development.
• 1.4 The FIH Trial.
• 1.5 The Regulatory Landscape.
• 1.6 Contract Research Organizations (CROs).
• 1.7 Concluding Remairs to Introductory Perspectives.
• 1.8 References.

Part II: Lead Optimization Strategies.

2 ADME Strategies in Lead Optimization (Amin A. Nomeir).

• 1.1 Introduction.
• 1.2 Absorption.
• 1.3 Distribution.
• 1.4 Metabolism.
• 1.5 Excretion.
• 1.6 Pharmacokinetics.
• 1.7 Prioritizing ADME Screens.
• 1.8 In Silico ADME Screening.
• 1.9 The Promise of Metabolomics.
• 1.10 Conclusions.
• 1.11 References.

3 Prediction of Pharmacokinetics and Drug Safety in Humans (Peter L. Bullock).

• 1.12 Introduction.
• 1.13 Prediction of Human Pharmacokinetic Behavior.
• 1.14 Prediction of Drug Safety.
• 1.15 Conclusions.
• 1.16 References.

4 Bioanalytical Strategies (Christopher Kemper).

• 1.17 Introduction.
• 1.18 Basic Bioanalytical Techniques and Method Development.
• 1.19 Bioanalytical Method Validation.
• 1.20 Special Issues with Ligand Binding Assays.
• 1.21 Partial and Cross Validations.
• 1.22 Application of Validated Methods to Sample Analyses: Some.
• 1.23 Risk Based Paradigms: Discovery and Development Support.
• 1.24 Road to "First in Human".
• 1.25 International Perspectives.
• 1.26 Conclusions.
• 1.27 References.

Part III: Bridging from Discovery to Development.

5 Chemistry, Manufacturing and Controls - The Drug Substance and Formulated Drug Product (Örn Almarsson and Christopher J. Galli).

• 1.28 Introduction.
• 1.29 Pre-NCE Activities and NCE Development.
• 1.30 CMC Consideration at the NCE Stage.
• 1.31 NCE to GLP Transition (Bridging from Discovery to Pre-FIH Development).
• 1.32 CMCs to Meet Clinical Trial Material (CTM) Requirements.
• 1.33 CMC Strategic Considerations.
• 1.34 Case Studies.
• 1.35 Evolution of Drug Development in the 21st Century: Implications for CMCs in the Future.
• 1.36 Resources.
• 1.37 References.

6 Preclinical Safety Pharmacology Studies Recommended for Supporting First-in-Human (FIH) Clinical Trials (Duane B. Lakings).

• 1.38 Introduction and Overview.
• 1.39 Timing of Safety Pharmacology Studies.
• 1.40 CNS Safety Pharmacology.
• 1.41 Cardiovascular Safety Pharmacology.
• 1.42 Respiratory System Safety Pharmacology.
• 1.43 Renal/Urinary Safety Pharmacology.
• 1.44 Gastrointestinal System Safety Pharmacology.
• 1.45 Autonomic Nervous System Safety Pharmacology.
• 1.46 Other Systems.
• 1.47 Discussion and Conclusion.
• 1.48 References.

Part IV: Pre-IND Drug Development.

7 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).

• 1.49 Introduction.
• 1.50 Toxicology Support of Discovery.
• 1.51 Goals of the Pre-FIH Toxicology Program.
• 1.52 Importance of a Clinical Review of the Nonclinical Pharmacology Data.
• 1.53 Take the Time to Plan Appropriately.
• 1.54 The Active Pharmaceutical Ingredient (API).
• 1.55 Timely Conduct of In Vitro Assays.
• 1.56 Development of Validated Bioanalytical and Analytical Assays.
• 1.57 Planning for the Conduct of Toxicity Studies.
• 1.59 The Pre-IND Meeting.
• 1.60 Conclusion.
• 1.61 References.

8 Toxicokinetics in Support of Drug Development (Gary Eichenbaum, Vangala Subrahmanyam and Alfred Tonelli).

• 1.62 Introduction.
• 1.63 Historical Perspectives.
• 1.64 Regulatory Considerations.
• 1.65 Factors to Consider in the Design of Toxicokinetic Studies.
• 1.66 Toxicokinetic Parameter Estimates and Calculations.
• 1.67 Interpretation of Toxicokinetic Data.
• 1.68 Role of Toxicokinetics in Different Types of Toxicity Studies.
• 1.69 Role of Toxicokinetics in Integrated Safety Assessment.
• 1.70 Conclusion.
• 1.71 References.

9 Good Laboratory Practices (Anthony B. Jones, Kathryn Hackett-Fields and Shari L. Perlstein).

• 1.72 Introduction.
• 1.73 Hazard and Risk.
• 1.74 The US GLP Regulations.
• 1.75 GLPs in the Bioanalytical Laboratory.
• 1.76 Moving into the Future: a Closing Overview.
• 1.77 Acknowledgements.
• 1.78 Appendices.
• 1.79 References.

10 Estimation of Starting Dose for Phase I Clinical Programs (Lorrene A. Buckley, Parag Garhyan, Rafael Ponce and Stanley A. Roberts).

• 1.80 Introduction.
• 1.81 Characteristics of Well Behaved Therapeutic Candidates.
• 1.82 Regulatory Guidances for FIH-Enabling Preclinical Safety Assessment: General Principles.
• 1.83 Preclinical Pharmacokinetics (PK) and Pharmacodynamics (PD) for Human Dose Projection.
• 1.84 Establishing the First-in-Human Dose.
• 1.85 Phase I Clinical Trial Support: Use of MABEL or Pharmacologically Active Dose (PAD).
• 1.86 Support of ?Exploratory? Clinical Studies.
• 1.87 Considerations in the Design of Phase I Trials.
• 1.88 Interdisciplinary Partnerships.
• 1.89 Beyond the FIH Dose.
• 1.90 Concluding Perspective.
• 1.91 Four Case Studies.
• 1.92 Acknowledgements.
• 1.93 References.

Part V: Planning the First-in-Human Study and Regulatory Submission.

11 Exploratory INDs/CTAs (Mitchell N. Cayen).

• 1.94 Introduction.
• 1.95 Regulatory Background.
• 1.96 Experience and Various Perspectives on ExpINDs or ExpCTAs.
• 1.97 Some Reactions and Perspectives on the ExpIND/ExpCTA Initiative.
• 1.98 What is an Ideal Candidate for an ExpIND/ExpCTA?
• 1.99 Conclusions.
• 1.100 Acknowledgements.
• 1.101 References.

12 Unique Considerations for Biopharmaceutics (Laura P. Andrews and James D. Green).

• 1.102 Introduction and Background.
• 1.103 election of the Molecule: Contrasts to Small Molecule Considerations.
• 1.104 Production and Process Considerations in Pre-FIH Development.
• 1.105 Bioanalytical Assay Considerations.
• 1.106 Objectives and Implementation of Pre-FIH Safety Assessment Programs.
• 1.107 Post-IND Considerations: Support of Phase II, III and Registration.
• 1.108 The TeGenero Incident and Implications for Biopharmaceutic Preclinical Safety Evaluation Programs.
• 1.109 Conclusions.
• 1.110 References.

13 Project Management and International Regulatory Requirements for First-in-Human Trials (Carolyn D. Finkle and Judith Atkins).

• 1.111 Introduction: Initiate Product Development with the "End in Mind".
• 1.112 Importance of Project Management.
• 1.113 FDA Input Early and Often.
• 1.114 The (US) IND Submission.
• 1.115 Global Clinical Trials.
• 1.116 The Clinical Trial Application (CTA).
• 1.117 Conclusion.
• 1.118 References.

14 First-in-Human Regulatory Submissions (Mary Sommer, Mark Ammann, Ulf Hillgren, Kathleen Kovacs and Keith Wilner).

• 1.119 Introduction.
• 1.120 Submission Strategies.
• 1.121 First-in-Human Dossiers.
• 1.122 United States: Investigational New Drug Application (IND).
• 1.123 European Union: Clinical Trial Application (CTA).
• 1.124 Japan: Clinical Trial Protocol Notification (CTPN).
• 1.125 Emerging Regions.
• 1.126 Biopharmaceuticals.
• 1.127 Final Considerations.

Appendix 1: List of Abbreviations.
Appendix 2: Definitions and Glossary of Terms.
Appendix 3: Some Relevant Government and Regulatory Documents.
Appendix 4: Some Relevant Resources with Web Sites.

Author Information

MITCHELL N. CAYEN, PhD, is Principal of Cayen Pharmaceutical Consulting, LLC, a firm that advises pharmaceutical companies in nonclinical and clinical drug develop-ment, with specific focus on candidate drug selection, discovery, drug metabolism and pharmacokinetics, drug development strategies, and regulatory submissions. Previously, he was senior director of drug metabolism and pharmacokinetics at Schering-Plough Research Institute.