Cover -- Title page -- Copyright page -- Contents -- Contributors -- The editors -- Acknowledgements -- List of abbreviations -- Preface -- Part I: Research and development -- 1: Discovery of new medicines -- Introduction -- Medicines marketed in the years 2008-2011 -- Impact of high throughput screening in drug discovery -- Impact of combinatorial chemistry on drug discovery -- Fragment-based design -- Examples in drug discovery -- Hepatitis C virus -- HIV -- Central nervous system therapeutic area -- Alzheimer's disease -- Cardiovascular disease -- Chronic obstructive pulmonary disease -- Diabetes -- Osteoporosis -- Gastrointestinal diseases -- Oligonucleotide-based therapeutics -- Orphan diseases -- Neglected tropical diseases -- Recent drug discovery strategies to improve success -- Natural products in drug discovery -- Drug repositioning -- The new role of academia in pharmaceuticals -- Conclusions -- References -- 2: Pharmaceutical development -- Introduction -- Role of analytical method development -- Role of regulatory control -- Drug delivery -- Local or systemic delivery -- Instant or extended release -- Absorption enhancement -- Product formulation types -- Oral solids -- Oral liquids -- Sterile products -- Pulmonary delivery -- Other formulation types -- Concluding remarks on formulation selection -- Quality by Design -- The concept of Quality by Design -- Implementation of Quality by Design -- Drug substance properties at the preclinical testing stage -- Principles of pharmaceutical development -- Oral solid dosage form development -- Oral solid dosage components -- Key oral solid dosage processes -- Oral solid dosage manufacturing -- Sterile products -- Sterile product manufacturing -- Sterile product design -- Stability of parenterals -- Conclusions -- 3: Preclinical safety testing -- Introduction -- The 'omic' technologies.

The drug development process -- Risk-benefit -- Good Laboratory Practice -- Preclinical safety pharmacology -- Regulatory guidelines -- General considerations -- Experimental design -- Safety pharmacology core battery -- Single-dose studies -- Repeat-dose studies -- Maximum repeatable dose study to obtain information about the maximum tolerated dose -- Definitive repeat-dose toxicity studies -- Carcinogenicity studies -- Route of administration -- Dose selection -- Group sizes -- Conduct of study -- Duration of study -- Autopsy and microscopic examination -- Evaluation of results -- Reproductive toxicology -- Aims of studies -- Types of studies -- Timing of studies -- Juvenile toxicity studies -- Evaluation and interpretation of data -- Genotoxicity testing -- Study design -- Germ cell tests -- Study interpretation -- Irritation and sensitisation testing -- Irritancy -- Immunotoxicology -- Special routes -- Specialty areas -- Scaling from animals to humans -- Specific considerations for biologicals -- Animal numbers, costs and ethics -- References -- 4: Exploratory development -- Introduction -- Definitions -- Objectives of exploratory development -- Outcomes of exploratory development -- Planning exploratory development -- The need for a regulatory strategy -- Devising the plan -- Presentation of the plan -- Requirements for administration of an NME to humans -- Evidence of primary pharmacodynamic activity -- Secondary pharmacodynamic activity and safety pharmacology -- Pharmacokinetics and drug metabolism -- Toxicology -- Drug substance and pharmaceutical formulations -- Preparation for the first administration to humans -- Transfer from preclinical to clinical -- Preparation of the Investigator's Brochure -- Aspects of the first protocol and ethics review -- Request for clinical trial authorisation -- Studies in healthy volunteers.

What is a healthy (non-patient) volunteer? -- Healthy volunteers or patients? -- Source of healthy volunteers -- Facilities and staff -- Volunteer recruitment procedures -- Good Clinical Practice -- Adverse reactions in volunteer studies -- Insurance and compensation -- Objectives of first-in-human studies -- Tolerability and safety -- Pharmacokinetics -- Pharmacodynamics -- Design of the first-in-human study -- Choice of dose range -- Magnitude of dose increments -- Should we dose to toxicity? -- Number of doses for individual subjects -- Use of placebo -- Blinding -- Parallel groups or crossover -- Size of cohorts -- Minimising risk -- Minimal risk -- Practical aspects of study design and conduct -- Interim reviews -- Higher risk new molecular entities -- Subsequent studies in exploratory development -- Effect of food ingestion -- Repeat doses -- Studies in the elderly -- Drug interactions -- Mass-balance studies -- Surrogate endpoints for dose-response in patients -- Outcomes of ED -- References -- 5: Clinical pharmacokinetics -- Introduction -- Basic concepts -- Overview of the fate of administered drug -- Plasma concentration-time curve -- Descriptive versus conceptual parameters -- Predictions from pharmacokinetic parameters -- Use of pharmacokinetic information to design dosage regimens -- Bioavailability and bioequivalence -- Bioavailability -- Bioequivalence -- Drug interactions -- Selection of studies -- Study design -- Enzyme induction and inhibition -- Protein binding -- The elderly -- Renal impairment -- Liver disease -- Disposition, rates and routes of elimination of radiolabelled drug -- Pharmacokinetic-pharmacodynamic modelling -- Population analysis -- The rest of the typical clinical pharmacokinetics package -- The ideal drug from the point of view of pharmacokinetics.

Role of pharmacokinetic properties in determining a dosage regimen -- Conclusions -- References -- 6: Biological therapeutics -- Introduction - the history of biologics development -- Differences between 'chemical' and 'biological' molecules -- Monoclonal antibody against a soluble ligand target -- Monoclonal antibody against a cell surface target -- Immunogenicity -- First-in-human dose selection for a biologic -- Conclusions -- References -- 7: Objectives and design of clinical trials -- History of the controlled clinical trial -- Objectives of clinical trials in drug development -- Design of controlled clinical trials -- Controls: placebo and active comparators -- Blinding -- Primary and secondary endpoints -- Surrogate and clinical endpoints -- Parallel and crossover trials -- Randomisation -- Selection of dosage -- Special populations -- Analysis of controlled clinical trials -- Hypothesis testing, power and p-values -- Confidence intervals -- Odds ratios, absolute and relative risk -- Final word -- References -- Further reading -- Control groups in clinical trials -- Statistical aspects of study design and analysis -- 8: Conduct of clinical trials: Good Clinical Practice -- Introduction -- Good Clinical Practice -- Declaration of Helsinki -- ICH GCP -- EU Clinical Trials Directive (2001/20/EC) and EU GCP Directive (2005/28/EC) -- Preparation of documentation for the clinical trial -- The trial master files -- The IMP and its documents -- Manufacture -- Comparators -- Presentation -- Shipping and importation -- Control and documentation of IMP -- Running the clinical trial -- Before the start of the trial -- Technical considerations -- During the trial -- Data management -- Preparation of the clinical report -- General considerations -- Quality management -- Quality control and quality assurance -- Fraud and misconduct -- Conclusions.

References -- Further reading -- Useful internet addresses -- 9: Medical statistics -- Introduction -- Probability -- What is probability? -- Inductive probability -- Scales of measurement and clinical endpoints -- Qualitative data -- Quantitative data -- Measurement and endpoints -- Basic statistical principles -- Descriptive statistics -- Inferential statistics -- Issues in design -- Study aims and objectives -- Explanatory/pragmatic trials -- Choice of endpoint -- Prevention of bias -- Control groups -- Active control groups -- Choice of analysis -- Sample size and power calculations -- Meta-analysis and summaries -- Uses of meta-analysis and their strengths and weaknesses -- References -- 10: Development of medicines: full development -- Introduction -- Background -- Senior management perspective -- Taking products into later development phase -- Clinical perspective -- Regulatory perspective -- Commercial perspective -- Exit strategy -- Preparing the plan -- Structure of the plan -- Therapeutic targets -- Safety -- The detailed clinical development plan -- Number of patients -- Number of studies -- Patient categories -- Coexisting medical conditions and concomitant drug interactions -- Duration of treatment -- Dose -- Dosage form -- Clinical trial supplies -- Length of the programme -- Data management -- Cost -- Technology -- Executing the plan -- Contract research organisations -- Selection of sites -- Prioritisation of trials -- Quality management -- Process improvement -- Communication -- Training -- Acknowledgements -- References -- 11: Pharmacovigilance -- Introduction -- Benefit and risk -- The wider context -- The pharmacovigilance process -- Legislation and the regulatory authorities -- Legislation -- Regulatory authorities -- Qualified Person for Pharmacovigilance -- Harmonisation initiatives -- CIOMS working groups and reports.

Contribution of ICH to safety surveillance.