Mann's Pharmacovigilance

Elizabeth B. Andrews, Nicholas Moore, Elizabeth B. Andrews, Nicholas Moore

• Publisher: Wiley-Blackwell
• Year: 2014
• Print ISBN: 9780470671047
• eBook ISBN: 9781118820148
• Edition: 3
• Topic: Medicine
• Subtopic: Pharmacology

Highly Commended at the BMA Medical Book Awards 2015

Mann's Pharmacovigilance is the definitive reference for the science of detection, assessment, understanding and prevention of the adverse effects of medicines, including vaccines and biologics.

Pharmacovigilance is increasingly important in improving drug safety for patients and reducing risk within the practice of pharmaceutical medicine. This new third edition covers the regulatory basis and the practice of pharmacovigilance and spontaneous adverse event reporting throughout the world. It examines signal detection and analysis, including the use of population-based databases and pharmacoepidemiological methodologies to proactively monitor for and assess safety signals. It includes chapters on drug safety practice in specific organ classes, special populations and special products, and new developments in the field.

From an international team of expert editors and contributors, Mann's Pharmacovigilance is a reference for everyone working within pharmaceutical companies, contract research organisations and medicine regulatory agencies, and for all researchers and students of pharmaceutical medicine.

The book has been renamed in honor of Professor Ronald Mann, whose vision and leadership brought the first two editions into being, and who dedicated his long career to improving the safety and safe use of medicines.

1
Introduction: Updated from Second Edition

Ronald D. Mann

University of Southampton, Waterlooville, Hampshire, UK

Elizabeth B. Andrews

RTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA and School of Public Health and School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA

Background

Pharmacovigilance – the study of the safety of marketed drugs under the practical conditions of clinical use in large communities – involves the paradox that what is probably the most highly regulated industry in the world is, from time to time, forced to remove approved and licensed products from the market because of clinical toxicity. Why is such close regulation not effective in preventing the withdrawal of licensed products? The question has been with us from the very early days of the 1960s and remains with us today, and its consideration tells us a great deal about pharmacovigilance.

The greatest of all drug disasters was the thalidomide tragedy of 1961–1962. Thalidomide had been introduced, and welcomed, as a safe and effective hypnotic and anti-emetic. It rapidly became popular for the treatment of nausea and vomiting in early pregnancy. Tragically, the drug proved to be a potent human teratogen that caused major birth defects in an estimated 10 000 children in the countries in which it was widely used in pregnant women. The story of this disaster has been reviewed elsewhere (Mann, 1984).

The thalidomide disaster led, in Europe and elsewhere, to the establishment of the drug regulatory mechanisms of today. These mechanisms require that new drugs shall be licensed by well-established regulatory authorities before being introduced into clinical use. This, it might be thought, would have made medicines safe – or, at least, acceptably safe. But Table 1.1 summarizes a list of 46 licensed medicines withdrawn, after marketing, for drug safety reasons since the mid 1970s in the UK.

Table 1.1 Drugs withdrawn in the UK by the marketing authorization holder or suspended or revoked by the Licensing Authority, 1975–2010.

Brand name (drug substance)	Year action taken	Major safety concern
Secholex (polidexide)	1975	Safety concerns because of impurities
Eraldin (practolol)	1975	Oculomucocutaneous syndrome
Opren (benoxaprofen)	1982	Hepatotoxicity, serious skin reactions
Devryl (clomacran phosphate)	1982	Hepatotoxicity
Flosint (indoprofen)	1982	Gastrointestinal toxicity
Zomax (zomepirac)	1983	Anaphylaxis
Osmosin (indomethacin-modified release)	1983	Small-intestine perforations
Zelmid (zimeldine)	1983	Neurotoxicity
Flenac (fenclofenac)	1984	Lyell's syndrome
Methrazone (feprazone)	1984	Serious skin reactions, multisystem toxicity
Althesin (alphaxolone plus alphadolone)	1984	Anaphylaxis
Pexid (perhexilene)	1985	Hepatotoxicity, neurotoxicity
Suprol (suprofen)	1986	Nephrotoxicity
Merital (nomifensine)	1986	Hemolytic anemia
Unicard (dilevalol)	1990	Hepatotoxicity
Glauline eye drops 0.6% (metipranolol)	1990	Uveitis
Halcion (triazolam)	1991	Psychiatric reactions
Micturin (terodiline)	1991	Arrhythmias
Teflox (temafloxacin)	1992	Multisystem toxicity
Centoxin (nebacumab)	1993	Mortality
Roxiam (remoxipride)	1994	Aplastic anemia
Volital (pemolin)	1997	Hepatotoxicity
Romazin (troglitazone)	1997	Hepatotoxicity
Serdolect (sertindole)	1998	Arrhythmias
Tasmar (tolcapone)	1998	Hepatotoxicity
Ponderax (fenfluramine)	1998	Cardiac valvular disease
Adifax (dexfenfluramine)	1998	Cardiac valvular disease
Posicor (mibefradil)	1998	Drug interactions
Trovan (trovafloxacin)	1999	Hepatotoxicity
Grepafloxacin (Raxar)	1999	QT interval prolongation
Prepulsid (cisapide)	2000	QT interval prolongation
Alec (pumactant)	2000	Adverse comparative trial results
Droleptan (droperidol)	2001	Increased cardiac risks
Lipobay (cerivastatin)	2001	Rhabdomyolysis
Kava-Kava	2001	Liver toxicity
Anorectic agents (amfepramone, phentermine)	2000	Heart valve disorders
Vioxx (rofecoxib)	2004	Increased cardiovascular event risks
Non-proprietary (co-proxamol)	2005	Use in suicide
Bextra (valdecoxib)	2005	Stevens–Johnson syndrome
Prexige (lumiracoxib)	2007	Hepatotoxicity
Carisoma (carisoprodol)	2007	Abuse potential
Trasylol (aprotinin)	2007	Death following cardiac surgery
Accomplia (rimonabant)	2008	Depression, Suicide
Raptiva (efalizumab)	2009	Progressive Multifocus Leukoencephalopathy
Reductil (sibutramine)	2010	Cardiovascular mortality
Avandia (rosiglitazone)	2010	Increased cardiovascular event risk

Why should the highly regulated pharmaceu­­tical industry need, or be compelled, to withdraw licensed medicines for drug safety reasons? Why do these problems of licensed products being found toxic continue despite the accumulated experience of more than 50 years since the thalidomide tragedy?

Partly, the problem is one of numbers. For example, the median number of patients contributing data to the clinical safety section of new drug licensing applications in the UK is only just over 1500 (Rawlins and Jefferys, 1991). Increasing regulatory demands for additional information before approval have presumably increased the average numbers of patients in applications, especially for new chemical entities; nevertheless, the numbers remain far too small to detect uncommon or rare adverse drug reactions (ADRs), even if these are serious.

The size of the licensing applications for important new drugs cannot be materially increased without delaying the marketing of new drugs to an extent damaging to diseased patients. Thus, because of this problem with numbers, drug safety depends very largely on the surveillance of medicines once they have been marketed.

A second reason for difficulty is that the kinds of patients who receive licensed medicines are very different from the kinds of volunteers and patients in whom premarketing clinical trials are undertaken. The patients in formal clinical trials almost always have only one disease being treated with one drug. The drug, once licensed, is likely to be used in an older group of patients, many of whom will have more than one disease and be treated by polypharmacy. The drug may also be used in pediatric patients, who are generally excluded from initial clinical trials. The formal clinical trials may be a better test of efficacy than they are of safety under the practical conditions of everyday clinical usage.

A third problem is that doctors may be slow or ineffective in detecting and reporting adverse drug effects. Many of the drugs summarized in Table 1.1 were in widespread, long-term use before adverse reactions were detected, and even now hospital admissions due to ADRs have shown an incidence of between 2.4% and 3.6% of all admissions in Australia, with similar or greater figures in France and the USA (Pouyanne et al., 2000). Even physicians astute in detecting adverse dru...

Table of contents

• Cover
• Table of Contents
• Title page
• Copyright page
• Contributors
• Foreword
• 1: Introduction: Updated from Second Edition
• 2: History of Pharmacovigilance
• Part I: The Regulatory Basis of Pharmacovigilance
• Part II: Pharmacovigilance Systems
• Part III: Signal Detection/Generation in Spontaneous Reporting Programs and Other Sources: From Spontaneous Reporting to Pharmacoepidemiology
• Part IV: Pharmacovigilance and Drug/System Organ Classes
• Part V: Current Topics
• Part VI: Training and Education and Directions
• Supplemental Images
• Index
• End User License Agreement