新藥開發手法：第3版

Abstract

The first version of this aid to understanding pharmaceutical R&D was published in 2003 and updated in 2005. It concentrated on small molecule drugs (molecular weights usually below 500 daltons) and the dangers of failing to integrate their discovery with the developmental demands of clinical research (pharmaceutics, pharmacokinetics and safety, for example). Aimed at no particular specialists, it sought to inform all those involved with pharmaceutical R&D, however loosely, how each of the necessary disciplines fit together to take a new medicine from discovery to market launch. Feedback was positive but with one consistent request: to increase the detail on regulatory procedures and clinical evaluation. Version 2 was published in 2005 with this aim.

A second update is timely from several standpoints. True, the principles of R&D have not changed markedly in the intervening years, but like any industry, Pharma has been forced to take stock of the manner in which it operates. Analysis of financial profits and losses consistently shows that increasingly greater investment is required for reduced numbers of marketed products. Despite the introduction of new technologies aimed at faster and more innovative drug discovery, the number of new introductions with novel mechanisms of action has remained constant. And threats to public safety, whilst rare, demand ever more stringent regulatory procedures.

The industry continues to consolidate through M&A. Although these activities in themselves rarely bring long-term growth, they provide an opportunity to divest activities no longer considered essential for in-house ownership. From this has sprung the need for contract organisations, specialist companies with expertise in particular phases of pharmaceutical R&D ranging from the supply of drug targets and chemical building blocks through non-clinical development and on to clinical evaluation and regulatory affairs.

Innovation in the industry is not at a standstill: it has changed direction. Where once small molecule research provided the mainstay, biological drugs are now making their presence felt. While the range of genomic sciences waits to make its impact, biologicals are providing the current focus for novel discovery. This move doesn' t come without a price. Biologicals do not behave like small molecules: they have large molecular weights and are most usually species specific. The rules for their development are different and often little understood: witness the tragedy which occurred at Northwick Park following the administration of an immune activator to healthy volunteers in March 2006.

The 2007 update to ‘How Drugs are Developed’ responds to these changes. Sections which previously focused on small molecules have been expanded where necessary to describe the corresponding processes for biologicals. And there are two new chapters. The first deals with project management: the fundamentals of managing multidisciplinary teams and the ways in which the role is changing to encompass external as well as internal interfaces. The second concerns the growing interest in translational research, the ways in which laboratory concepts can be converted into medical advances.

In 2003, the impact of sequencing the human genome was just being felt throughout the industry. Now, in 2007, it is apparent that while providing promise for the future, there will be no ' quick fix' for the industry and it must pursue an ever wider range of opportunities to achieve its goals. The result is a networked industry without historical parallel.

Table of Contents

INTRODUCTION

CHAPTER 1 DRUG TARGETS AND TARGET HUNTING

• 1.1 Target hunting
  • 1.1.1 Proteins as drug targets
  • 1.1.2 Enzymes and the significance of protein folding
  • 1.1.3 Protein synthesis
  • 1.1.4 Further processing of proteins
• 1.2 The range of drug targets
  • 1.2.1 Bioinformatics
  • 1.2.2 Systems biology
  • 1.2.3 Metabonomics
• 1.3 The range of drugs
  • 1.3.1 Enzyme inhibition
  • 1.3.2 7-transmembrane receptors (7TMs)

CHAPTER 2 LEAD GENERATION

• 2.1 Introduction
• 2.2 Small molecule lead generation
  • 2.2.1 Units
  • 2.2.2 Lead generation strategies
  • 2.2.3 Lipinski' s rule of 5
  • . . . molecular size
  • . . . fatty/aqueous considerations
  • . . . hydrogen bonding
  • 2.2.4 Fragment-based lead generation
  • 2.2.5 Chemi-informatic filters
• 2.3 Practical lead generation
  • 2.3.1 High throughput screening (HTS)
  • 2.3.2 Receptor binding assays
• 2.4 Combinatorial chemistry
• 2.5 Parallel synthesis
• 2.6 Structure/activity relationships (SARs)
• 2.7 SAR, quantified structure/activity relationships and CADD
• 2.8 Secondary screening
• 2.9 Biotechnology and lead generation
  • 2.9.1 Mimicry of the natural ligand
  • 2.9.2 Recombinant technology
  • 2.9.3 Recombinant Factor VIII
  • 2.9.4 Recombinant erythropoietin
  • 2.9.5 Monoclonal antibodies
  • 2.9.6 Monoclonal antibodies and immunogenicity
  • 2.9.7 Mechanism of action
  • 2.9.8 Advantages and disadvantages of biological products versus small molecules

CHAPTER 3 LEAD OPTIMISATION

• 3.1 Early safety screening
  • 3.1.1 Genetic toxicity
  • 3.1.2 e-screens for genetic toxicity
  • 3.1.3 General toxicity screening
  • 3.1.4 Screening for genetic toxicity - the Ames test
  • 3.1.5 Mouse lymphoma assay (MLA)
  • 3.1.6 Clastogenicity
• 3.2 HTS bioavailability and pharmacokinetics
  • 3.2.1 Models of absorption
  • 3.2.2 Metabolism
  • 3.2.3 Optimisation of biologicals
• 3.3 Summary

CHAPTER 4 PREPARING FOR DEVELOPMENT

• 4.1 Patent filing
  • 4.1.1 Competitor surveillance
• 4.2 Optimisation for potency
• 4.3 In vivo activity
• 4.4 Therapeutic ratio and a consistent drug delivery
• 4.5 Efficacy, toxicity and dose consistency - the basis of preclinical research
• 4.6 In search of dosing consistency
  • 4.6.1 The significance of low bioavailability
  • 4.6.2 Optimisation of bioavailability
  • . . . aqueous solubility
  • . . . particle crystallinity and size
  • . . . polymorphism
  • 4.6.3 Stability
  • 4.6.4 Salt formation
  • 4.6.5 Solution stability
• 4.7 Drug disposition and bioavailability
  • 4.7.1 Absorption and distribution
    • 4.7.1.1 Metabolism and excretion
    • . . . a metabolite may be more active than the parent
    • . . . enzyme inhibition, induction and polymorphism
    • . . . Phase-1 and Phase-2 metabolism
• 4.8 Pharmacokinetics (primer)
  • 4.8.1 Cassette dosing
  • 4.8.2 Absolute bioavailability
• 4.9 Drug safety
  • 4.9.1 Toxicogenomics
  • 4.9.2 Safety pharmacology
    • 4.9.2.1 Receptor and enzyme screening
    • 4.9.2.2 Cardiovascular toxicity
    • . . . HERG assay
    • . . . in vivo cardiovascular screening
    • 4.9.2.3 Respiratory system
    • 4.9.2.4 Central nervous system (CNS) screening
• 4.10 Good laboratory practice
• 4.11 Summary statements
• 4.12 Project progression criteria
  • 4.12.1 Target proposal
  • 4.12.2 Nomination of a lead
  • 4.12.3 Nomination of a development candidate
    • 4.12.3.1 Biology
    • 4.12.3.2 Patent
    • 4.12.3.3 Chemistry
    • 4.12.3.4 Pharmaceutics
    • 4.12.3.5 Drug disposition
    • 4.12.3.6 Safety
• 4.13 Preparing a biological candidate for development
  • 4.13.1 API preparation
  • 4.13.2 Biological drug quality and cell banking
  • 4.13.3 Bioreactors
  • 4.13.4 Clinical formulation
  • 4.13.5 Biologic progression criteria
• 4.14 The case for development

CHAPTER 5 PRECLINICAL RESEARCH

• 5.1 Introduction
• 5.2 Drug substance supplies (kilogram-scale chemistry and bioprocessors)
  • 5.2.1 Patents
  • 5.2.2 Environment
  • 5.2.3 Health and safety
  • 5.2.4 Raw material sourcing and pricing
  • 5.2.5 Scalability
  • 5.2.6 Optimisation
  • 5.2.7 Liaison with the pharmaceutical department
• 5.3 Good manufacturing practice (GMP)
• 5.4 Synthetic route optimisation
  • 5.4.1 The early synthetic route for fluoxetine
  • 5.4.2 The final (or manufacturing) route for fluoxetine
  • 5.4.3 Analytical sciences and impurities
  • 5.4.3.1 The importance of finalising the route to drug substance early
  • 5.4.4 Manufacture of biological drugs
  • 5.4.5 API specification
  • 5.4.6 Stability
• 5.5 Investigational medicinal product (IMP) development
  • 5.5.1 The oral dosage form
  • . . . direct compression
  • . . . dry granulation
  • . . . wet granulation
  • . . . tablet coating
  • 5.5.2 Intravenous dosage form
  • 5.5.3 Specifications and stability
• 5.6 Non-clinical safety assessment
  • 5.6.1 General toxicology
  • 5.6.2 The regulatory requirements for FIM
  • . . . toxicokinetics
  • . . . safety study outcomes
  • . . . late-stage safety development programme
  • 5.6.3 Reproductive toxicology
  • . . . embryo-foetal development (EFD) testing (segment II)
  • . . . fertility testing (segment I)
  • . . . peri and postnatal toxicity trials (segment III)
  • 5.6.4 Special considerations for biologicals
  • . . . pharmacokinetics
  • . . . immunotoxicity
  • 5.6.5 Genetic toxicity and carcinogenicity
  • . . . the Ames test for regulatory submission
  • . . . chromosomal aberration test
  • . . . in vivo clastogenicity testing
  • . . . carcinogenicity testing
  • 5.6.6 High-risk medicinal products
• 5.7 Drug disposition
  • 5.7.1 Pharmacokinetics
  • . . . bioavailability
  • . . . distribution
  • . . . elimination and clearance
  • . . . therapeutic window
  • . . . PK/PD modelling
  • 5.7.2 ADME
  • . . . multi-resistance drug protein (MDR)
  • . . . blood-brain barrier
  • . . . plasma protein binding
  • . . . distribution
  • . . . mass balance study
  • . . . tissue distribution studies
  • . . . bile elimination studies
  • . . . drug disposition as the linchpin of drug development

CHAPTER 6 TRANSLATIONAL RESEARCH

• 6.1 Introduction
  • 6.1.1 Proof of concept studies
  • 6.1.2 Biomarkers
  • 6.1.3 Translational research in oncology
  • 6.1.4 Translational research and safety
    • 6.1.4.1 The heart and the liver
    • 6.1.4.2 Translational research and metabolism

CHAPTER 7 PROJECT MANAGEMENT

• 7.1 Introduction
  • 7.1.1 The project team
  • 7.1.2 The kick-off meeting
  • 7.1.3 The project plan
  • 7.1.4 Maintaining progress
• 7.2 The project team as the company experts
• 7.3 Project teams as mediators of innovation
• 7.4 Project teams and outsourcing
• 7.5 Project managers

CHAPTER 8 REGULATORY SUBMISSIONS

• 8.1 Introduction - the regulatory bodies
  • 8.1.1 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
  • 8.1.2 The major regulatory bodies of the world
  • . . . European Agency for the Evaluation of Medicinal Products (EMEA)
  • . . . US Food and Drug Administration (FDA)
  • . . . the Japanese Ministry for Health, Labour and Welfare (MHLW)
• 8.2 Regulatory submissions
  • 8.2.1 Application to conduct a clinical trial
  • . . . clinical trial application in the US (IND)
  • . . . and Europe (CTA)
  • 8.2.2 Changes to the European system for application to conduct clinical trials
  • 8.2.4 The investigator' s brochure (IB)
• 8.3 Regulatory strategy
  • 8.3.1 Quality
  • 8.3.2 Preclinical safety
  • 8.3.3 Linking it all together
• 8.4 Application to market a new drug
  • 8.4.1 The European licensing system
  • . . . the centralised procedure
  • . . . the mutual recognition procedure
  • . . . national submissions
  • 8.4.2 The common technical document
  • 8.4.3 Electronic CTD submissions (e-CTD)
  • 8.4.4 Marketing applications in the US
  • 8.4.5 Special examples of drug approval processes
  • . . . accelerated approval
  • . . . orphan drug status

CHAPTER 9 CLINICAL EVALUATION

• 9.1 Introduction
• 9.2 Definitions
• 9.3 Clinical trial regulation
  • 9.3.1 Ethics committee approval
  • 9.3.2 The clinical team
  • 9.3.3 Required documentation
• 9.4 The categories of clinical trials
  • 9.4.1 Characteristics of Phase I trials
  • . . . ADME parameters
  • . . . blood biochemistry
  • . . . dose escalation, single and multiple dose studies
  • 9.4.2 Clinical pharmacokinetics
  • . . . Phase I PK monitoring
  • . . . human microdosing
  • . . . PK trials for specific purposes
  • . . . the elderly
  • . . . paediatrics
  • . . . interaction with food
  • . . . bioequivalence trials
  • . . . specific population groups
• 9.5 Phase II studies
• 9.6 Phase II/III Go/NoGo
• . . . reasons for a project NoGo before Phase III
• 9.7 Phase III
  • 9.7.1 Characteristics of Phase III trials
  • 9.7.2 Example - rimonabant in Phase III
• 9.8 Pharmacoeconomics
  • 9.8.1 Trials with pharmacoeconomic endpoints
  • 9.8.2 Assessing technological advances
  • 9.8.3 The basis of NICE analyses
• 9.9 Concluding summary

CHAPTER 10 POSTMARKETING SURVEILLANCE (PMS)

• 10.1 Introduction
• 10.2 The need for PMS
• 10.3 Pharmacovigilance
  • 10.3.1 Drug safety
  • 10.3.2 Risk/benefit assessment
  • . . . evaluating risk
  • . . . evaluating benefit
• 10.4 The mechanics of pharmacovigilance
  • 10.4.1 PSURs
  • 10.4.2 Expedited reports
• 10.5 Risk management
• 10.6 Pharmacovigilance specification
  • 10.6.1 Developmental data
  • 10.6.2 Class effects
  • 10.6.3 Drug interactions
  • 10.6.4 Less obvious contingencies
• 10.7 The risk management plan
  • 10.7.1 Risk management in Europe
  • 10.7.2 The withdrawal of Vioxx
  • 10.7.3 Rimonabant

LIST OF TABLES

• Table 2.1 Units of molarity in decreasing concentration
• Table 2.2 Example of structure/activity table for hypothetical molecule
• Table 5.1 Example of specification for final API

LIST OF FIGURES

• Figure 1.1 Amino acid structure illustrating amino group and carboxylic acid by which peptide bonds and chains of amino acids are formed
• Figure 1.2 A sequence of amino acids linked through peptide bonds to form a peptide (a mini protein)
• Figure 1.3 The structure of myoglobin, a muscle protein rich in secondary folding characterised as a-helices
• Figure 1.4 Tertiary folding of protein chains in an imaginary enzyme
• Figure 1.5 The main steps of protein synthesis
• Figure 1.6 The essential elements of DNA
• Figure 1.7 Base pairing, the triplet code and protein synthesis
• Figure 1.8 Simplified illustration of the consequences of insulin receptor activation
• Figure 1.9 Principles of Serenex' s chemical genomics capability
• Figure 1.10 Illustration of cholesterol synthesis and control by HMGCoAR
• Figure 1.11 Nervous control of heart rate
• Figure 1.12 The generic cell and its drug targets
• Figure 2.1 Structural similarity between serotonin and sumatriptan
• Figure 2.2 The structures of cholesterol and lovastatin
• Figure 2.3 Computer model of ligand - protein interaction
• Figure 2.4 Charge change on amino acid with rising pH
• Figure 2.5 Illustration of hydrogen bond formation between water molecules
• Figure 2.6 Schematic of a sample receptor binding assay
• Figure 2.7 Illustration of 96-well microtitre plates, variants of which are used for combinatorial synthesis
• Figure 2.8 Combinatorial synthesis of hypothetical peptides
• Figure 2.9 The basic components of solid-phase combinatorial chemistry
• Figure 2.10 Representation of first stages of a solid-phase combinatorial synthetic plate
• Figure 2.11 Simplified network of intracellular enzyme activation
• Figure 2.12 Hypothetical proteins and their active sites
• Figure 2.13 Illustration of generation and joining of cohesive ends of two sequences to produce a new sequence
• Figure 2.14 Structure of an antibody
• Figure 2.15 Mechanism of action of Herceptin
• Figure 3.1 Safety studies likely to be included in lead generation and optimisation
• Figure 3.2 Possible outcomes from the Ames test
• Figure 3.3 Illustration of the barriers to drug absorption and distribution
• Figure 3.4 Intestinal cells grown to confluence to form a barrier between upper and lower chambers of culture wells
• Figure 3.5 Illustrative copy of various published datasets showing the correlation between human absorption and Papp for a series of known drugs
• Figure 4.1 The Eternal Triangle ................................................... efficacy, safety and dose delivery
• Figure 4.2 Schematic of the metabolism of a hypothetical drug
• Figure 4.3 Illustration of the entero-hepatic shunt and drug recycling
• Figure 4.4 Pharmacokinetic trace of hypothetical orally administered drug
• Figure 4.5 Pharmacokinetic trace of orally administered drug set against its in vitro potency
• Figure 4.6 Comparative pharmacokinetic curves for three development candidates
• Figure 4.7 Pharmacokinetic traces obtained for a drug following oral and iv dosing
• Figure 4.8 Relationship between Kr channel inhibition and terfenadine concentration
• Figure 5.1 The CDP as a stimulus and guide for preclinical development
• Figure 5.2 Simplified project plan around the time of candidate selection through to first in man (FIM) trials
• Figure 5.3 Early synthetic route for fluoxetine (Prozac)
• Figure 5.4 Final stage of synthesis of fluoxetine in manufacturing route
• Figure 5.5 The stages of pharmaceutical discovery and development
• Figure 5.6 Image of an infusion bag prepared for intravenous administration
• Figure 5.7 Schematic to show timing of major drug safety studies
• Figure 5.8 Illustration of a typical 28 day drug safety protocol
• Figure 5.9 Example of toxicokinetic data constructed from blood samples taken on Days 1 and 28 of a multiple dose safety study
• Figure 5.10 Comparison of toxicokinetics in rats and dogs
• Figure 5.11 Temporal arrangement of safety studies during the first 3-4 years of development
• Figure 5.12 Summary of the three aspects of reproductive toxicology
• Figure 5.13 Sample protocol for EFD study in the rat
• Figure 5.14 Chromosomal matching and identification of aberration in CHO cells
• Figure 5.15 Sigmoid - S-shaped - dose/response curve
• Figure 5.16 Schematic to show potential ADME fates of absorbed drugs
• Figure 5.17 An illustration of plasma protein binding
• Figure 5.18 Metabolic map containing a [14]C label in a metabolically stable position. Major metabolites can now be tracked and quantified through the determination of radioactive emissions
• Figure 5.19 Fundamental principles of a mass balance study using a radio-labelled drug substance
• Figure 5.20 Illustration of HMG CoA RI drug absorption through GI wall and return in the bile
• Figure 5.21 The eternal triangle revisited
• Figure 6.1 Comparative effects of an NME and budesonide for their ability to induce vasoconstriction in human forearm skin
• Figure 6.2 Graphs to show effects of PDE4 inhibitor upon TNFa generation and the induction of nausea
• Figure 8.1 Comparison of US and UK regulatory procedures before May 2004
• Figure 8.2 Four levels of application recognised by the EMEA to market new medical products
• Figure 8.3 Generic format of the common technical document
• Figure 10.1 The changing emphasis of drug safety responsibilities