Viewpoint Parts 1 - Uppsala Monitoring Centre

The Risks of Being AliveLiving is not a safe occupation. There arepotential hazards for each of us rangingfrom the activity of the tiniest microorganismsto the threat of global or cosmiccatastrophe. Even our homes are full ofhazards and great numbers of accidentsand misadventures happen in them.Driving a motor vehicle or being apassenger in one is amongst the mostdangerous of everyday activities.All of us engage in risky activity everyday of our lives, but we willingly orunthinkingly live with risk. We knowinglyaccept risks if:• the probability of something harmfulhappening is small or distant in time, or• the possible harmful event is not serious• the possible benefits are sufficientlystrong.We may well put caution aside and act inspite of possible or suspected risk.However, most of us are less willing tolive with risk if:• the probability of harm is high, or• the probable harm is serious, or• we are not in direct control and the riskis officially assessed and managed bypeople we do not know, by criteria wemay not know or share (drugs or foodstandards, for example).For each of us those risk assessments aredifferent and we each apply differentcriteria to different kinds of risks.Perception of risk is affected by manyvariables from the tiny workings of individualpsychology through to the sweepinginfluences of language and culture.Reducing RiskIn recent years there has been increasingpublic pressure to reduce risk and consequentialharm and improve safety. Lawsrequiring the wearing of seat-belts andcrash-helmets represent one kind ofmeasure; standards for food and domesticpower supplies are two others. Noamount of legislation, of course, willeliminate risk any more than litigationwill eliminate human error.Each of us is expected to take responsibilityfor the levels of risk we are willingto live with in areas over which we havecontrol. Governments are expected totake responsibility for risks which wemust live with in areas over which we donot have direct control (aircraft safetyand food production, for example) andsome areas which are within our control(permitted levels of alcohol in the bloodof drivers, for example).When we make decisions about ouractivities we do so on the basis of acalculation or an instinctive perceptionor judgement of the risks (and potentialharm) as well as potential benefits. Somepeople do things even when they knowthe odds are stacked against them, whenThe passionate rock-climberlives with the knowledge thatthe chance of injury or death ishigh, but happily accommodatesthe risks as a small price topay for the excitementof overcoming themand achieving thephysically nearimpossiblethe probability is high and the potentialharm is great (smokers, for example).Risk-aversionHowever, a social climate which isincreasingly intolerant of risk, has createda tendency to seek absolute safety andsecurity. This has led to a trend of blamingand punishing those who are seen to bethe cause of accident or misadventure.Part of this results from an unwillingnessto accept that it is natural for accidentsto happen, and that there is always someuncertainty in all human activities, inspite of legislation or good intentions.Part of it results from the pressure onpoliticians and public servants to showthat they are in control of the variables ofexistence.Risk in MedicineSo what about medicines? We are much lesstolerant of risk in relation to medicines.Indeed, there is a common fantasy thatmedicine should be – can be – risk-free.We are particularly intolerant when we feelwe may not be given the full informationor when knowledge of risk emerges longafter exposure. Demands that risk shouldconscientiously be reduced to absoluteminimum are entirely proper, as is theexpectation that information about riskshould be openly and freely available.What about the miraculous remedy, the‘magic bullet’, the infallibility of doctors?What about the risks of medical treatment?• While medicines have led to majorimprovement in the treatment and controlof diseases, from the deadliest to themost trivial, they can also produceadverse effects on the human body• While many drugs are precisely targetedto the causes and mechanisms of disease,and are brilliantly effective in thatrespect, they may also–have minor or major negative effectson other parts of the body, or6

Benefit,Harm,Effectivenessin MedicineWhen we think about the risks of medicines, we need to relatethe discussion to our understanding of risk in our lives in general.Tens of millions of people worldwide take part in nationallotteries. The odds of winning are tiny (maybe 1:15,000,000 orless – comparable to the odds against a catastrophic collisionbetween the earth and an asteroid*); in other words the chancesof not winning are utterly overwhelming.Why do people do it? Because the dream of winning (someonewins, after all) is more pleasing than the almost certain loss of afew francs, dollars, or lire, cedis, pesos or baht and the usuallyminor harm to one’s personal finances. It’s a perverse activity:the pleasure of taking part in something with enormous potentialbenefit, though the odds against winning are staggeringly huge(much, much higher than the odds against being killed in a caraccident, which is relatively common).We make these judgements or calculations all the time:• what is the probability of benefit and how much can I expect?• what is the probability of damage and how severe and howlong?• how do I feel about the balance between them?Tough StandardsWe apply different criteria to drugs: we are much tougher inour demands for good odds against the occurrence of harm.Although the benefits of a drug to a significant proportion ofthe intended patients may be clear, a major crisis can arise whena few dozen people out of perhaps hundreds of thousandsreceiving the drug suffer or die as a result of taking it.to a substantial portion of the treated population, a relativelyinfrequent occurrence of harm may give rise to demands forthe drug to be restricted in use or withdrawn completely. Theauthorities make judgements on behalf of populations rather thanindividuals, usually on the basis of uncertain and incompleteinformation. Such action may leave individuals or groups ofindividuals significantly disadvantaged.This behaviour has to do with the very proper concern – indeedthe duty – of officials nationally and internationally to protectthe population from harm. Their commitment is such that theymay be panicked into radical action on the weakest of evidence.(On the other hand, even strong evidence sometimes takes yearsto lead to action of any kind – the harm caused by the drugpiroxicam and the massacre caused by traffic accidents, forexample.)Expressing RiskOur reactions to risk are also related to our poor understandingof probability and how levels of risk are expressed. A magazineheadline may say: ‘Risk of blood clotting doubles in new studyof drug X’ – and national panic follows. But what is the realitybehind the headlines?Absolute RiskThe absolute risk tells us the number of affected cases and thetotal number of people in the relevant population (e.g. for every1,000 skiers X will break a leg in any one year). If the studygroup is 10,000 people, then a doubling of risk from one caseto two cases is a very small numerical and percentage increase(from 1 in 10,000 to 2 in 10,000). If the study group is 1,000people, then an increase in cases from ten to twenty is also adoubling, but is a larger increase in numbers and percentage(from 10 in 1,000 to 20 in 1,000). The use of words like‘doubling’ or simple percentage figures can be very misleadingunless the total numbers are also given.A recent and damaging controversy concerned third generation oralcontraceptives. This arose from (a) careless use of the phrase ‘doublingof risk’ (relating to a very small suggested rise in risk of venousthromboembolism) coupled with (b) various disputed statistics. Theproblems (particularly of women abandoning the drug and of a risein abortions) were greatly increased by late or inadequate informationand communications involving doctors, patients and journalists.For an account of the issues, see: Mills A, Edwards IR. Venous thromboembolismand the pill. The combined oral contraceptive pill – are poorcommunication systems responsible for loss of confidence in thiscontraceptive method? Hum Reprod 1999;14(1). 7-10.* The probabilities and timescales involved, are quite different,however: in a lottery there is almost certain to be a winner and quitecertainly X million losers (depending on how many people buy tickets);with the asteroid it’s the risk of a remotely possible event occurringduring a very long period of time.Thus, even when a drug is known to provide significant benefitsRelative RiskThe relative risk provides a comparison in risk for the exposedpopulation and for the non-exposed population.8

Benefit, Harm, Effectiveness and Risk…the subjective assessment of benefit by the patient, which maybe very different, and will vary from patient to patient.(For more on this issue, please see page 19)(The exposed population could be those taking a new drug; thenon-exposed population those taking no drug at all, a placeboor another drug, for example.) This is calculated as a ratio.If the problem affects 5 in 5,000 in the exposed population, and5 in 10,000 in the non-exposed population, the relative risk is2:1 – a doubling of relative risk – but the ratio makes senseonly if the true extent of the risk is indicated by inclusion ofthe figures. In this case it is an increase in risk from 5 in10,000 to 5 in 5,000 (or 1 in 2,000 to 1 in 1,000). As withabsolute risk, ‘doubling’ or ‘100% increase’ can be misleadingand dangerous expressions on their own.Attributable RiskOur understanding of the risk of harm from a drug must also bequalified by knowledge of the extent of the identified problemin the population not taking the drug. Attributable risk is thedifference between the risk in an exposed population (theabsolute risk) and an unexposed population (the reference risk).Maybe a ‘background rate’ of thirteen in a thousand peoplewith the disease get skin rashes when they’re not taking anydrug. If there are thirteen patients experiencing skin rashes in astudy group of one thousand it’s unlikely that most cases werecaused by the drug. On the other hand, if there are twenty-tworashes in the study group, then there may be an increasedattributable risk, in this case – around 9 in 1,000.Communicating RiskMost people come across these matters through TV, newspapers,magazines and internet. Much of such material is written bypeople who do not necessarily know a lot about drugs, thenature of risk or medical practice. What they tell us may betrue, but it may also be only a part of the whole picture and,therefore, potentially very misleading.Risk ratios tell us only the probability of an event occurring.They do not tell us about the seriousness or extent of theprobable event, nor do they provide sensitive information toallow patients to decide if they feel the harm they might endureis outweighed by the benefits they are likely to enjoy.Quality of Life‘Benefits’ are often described in the medical literature only inrelation to the likely pharmacological effectiveness of the drugon the symptoms or the disease. They do not usually allow forSecrecyBut public concerns may also be justified: some drugs orinterventions may well be suspect or unacceptably risky. Inthe past, there has been a tendency for some regulators andmanufacturers to be secretive, and to disguise their sometimesinevitable uncertainty or ignorance. There may be incompatibilitybetween the goals of manufacturers’ commercial interests andpublic health. The evidence and reasoning for regulatory actionare very rarely made public. Such practices have contributed tolack of public confidence and have, sometimes, increased therisk of otherwise manageable events turning into crises.Everyone – especially those who report these matters in the media– needs to have a very clear and accurate understanding ofthe complexity of the issues, and of the inherent elements ofuncertainty in science. (See article on Communications andEducation, page 16, for more on this.)Formal definitions of the terms discussed in this article appear inthe glossary on page 22.Don’t be misled……by statements like ‘Doubling of risk’ or ‘A relative risk of 2:1’ – what reallymatters is the number of people involved (‘increase from one to two peoplein a thousand…’)Defining the terms• Benefits are commonly expressed as the proven therapeutic goodof a product, but should also include the patient’s subjectiveassessment of its effects• Risk is the probability of harm being caused, usually expressed as apercentage or ratio; the probability (chance, odds) of an occurrence• Harm is the nature and extent of the actual damage that could becaused. It should not be confused with risk• Effectiveness in pharmacovigilance expresses the probability of thedrug working as expected in the clinical setting (opposite to its risk)• Efficacy is used to express the capacity of the drug to work asintended in ideal experimental circumstancesHow common is common?In pharmacovigilance the following terms represent the variousprobabilities of an occurrence:Common or frequent: between 1 in 100 (1%) and 1 in 10 (10%)Uncommon or infrequent: between 1 in 1,000 (0.1%) and 1 in 100 (1%)Rare: 1 in 10,000 (0.01%) and 1 in 1,000 (0.1%)Source: Guidelines for Preparing Core Clinical Safety Information on Drugs –Report of CIOMS Working Group III. Geneva, WHO, 1995.9

…the risks of drugs?Although one can determine whether there isany association between a drug and an eventthrough pharmacoepidemiology, it cannotestablish whether or not there is a causalrelationship in each case, nor does it explainthe nature or mechanism of an ADR.Pharmacovigilance: This is thescience of collecting, monitoring, researchingand evaluating data on the effects of medicinaldrugs, biological products, herbals and traditionalmedicines with a view to identifyingnew information about adverse reactions andpreventing harm to patients.Such data comes primarily from ‘spontaneousreporting’ of information by health careprofessionals. Sometimes these will be effectswhich were not picked up in clinical trials.While its primary concern is to alert the worldto possible new safety hazards, it is alsoconcerned with enhancing medical therapywith new information and thinking aboutbenefit, harm, effectiveness and risk andsuch issues as rational prescribing and qualityof life criteria. (How pharmacovigilance worksis described in more detail on the next page.)Some of the problems…These are the controversial concerns ofresearchers about some aspects of academicpharmacoepidemiology:• Increasing secret work and non-sharing of data dueto contractual obligations with the private sector• Diversion of resources to ‘fringe’ medicine whereno basis for rational study investigation has beenpresented• In the desire to obtain funding, conducting studieswhere a predetermined outcome is desired andengineered as a service to the funding agency• Neglect by pharmacoepidemiologists of the plightof Third World consumers, where drug markets areoften unregulated and drug advertising grossly anddangerously misleading, and• Increasing control and setting of research prioritiesin pharmacoepidemiology by the private sector tofurther its needs, which are not always congruentwith public health goalsStolley PD, Laporte JR. The Public Health, the University,and Pharmacology. In: Strom BL, ed. Pharmacoepidemiology,3rd ed. Chichester, Wiley, 2000:82-83.Cost of ADRsIn the US, it has been estimated that each year 2.2 million hospitalised patientshave serious ADRs; 106,000 patients have fatal ADRs. Interpretation of the datais problematic, but it seems likely that many of these ADRs are in the categoryof ‘avoidable’ and do not reflect the intrinsic qualities of the drugs.Lazarou J, Pomeranz BH, Covey PN. Incidence of adverse drug reactions inhospitalized patients: a meta-analysis of prospective studies. Journal of AmericanMedical Association, 1998, 279:1200-1205.See also: Griffin JP. The cost of adverse drug reactions. Adverse Drug React ToxicolRev, 1997, 16(2):75-78.ADRs may be the 4 th to 6 th largest cause of death in the US. Hospital admissionsdue to ADRs may be more than 10% in some countries; up to 20% of healthcarebudgets may be spent on drug complications.Source: Safety of Medicines – A Guide to detecting and reporting adverse drugreactions. World Health Organization, 2002.Conclusions of an up-to-date study of US Drug-related Morbidityand MortalityOverall the cost of drug-related morbidity and mortality exceeded $177.4 billionin 2000. Hospital admissions accounted for nearly 70% ($121.5 billion) of totalcosts, followed by long-term admissions, which accounted for 18% ($32.8 billion)…Since 1995 the costs associated with drug-related problems (DRPs) have morethan doubled…the total cost of drug-related morbidity and mortality exceedsthe cost of the medications themselves. DRPs are increasingly recognised as aserious and urgent – but largely preventable – medical problem.Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost ofillness model. Journal of American Pharmaceutical Association, 2001, 41:192–9.International Reporting of ADRsthe UMC receives around 200,000 reports from member countries each year.Countries with the best reporting rates generate:• over 200 reports per 1,000,000 inhabitants per year. The average is around100/1,000,000• over 150 reports per 1,000 physicians per year. The average is around 50/1,000Source: Olsson S ed. National Pharmacovigilance Systems. Uppsala, the UMC, 1999.Clinical TrialsAround 6,400 clinical trials are thought to take place each year around theworld, prior to new drugs being brought to market. Including trials run afterdrugs are on the market, the figure may be nearer 10,000 per year. Informationbased on Centre for Medicines Research International figures quoted byDrugDev123 Ltd 2000.Epidemiology: From Greek epidemia among people. Usually referring toprevalence of disease in a population and Greek logos – word, speech, thought,and, hence theory or science11

Pharmacovigilance— The Great ChallengeThalidomide In the winter of 1961 the world experiencedthe infamous ‘thalidomide disaster’. Thalidomide wasmarketed as a mild hypnotic (sleeping drug) and as a remedyagainst morning-sickness for pregnant women. About fouryears after its launch, a dramatic increase was seen in severalcountries in the frequency of phocomelia, a previously rarebirth-defect which left babies without limbs or with seriousdeformities. Epidemiological studies established that the causewas exposure of the foetus to the drug during pregnancy.Had international data been collected at the time, the patternof seriously harmful adverse effects might have been noticedearlier.If hundreds of millions of people are taking drugs and othertherapeutic substances every day, how on earth do you find outif any of those people are having problems as a result?Medical vigilance is the key: every healthcare professional in theworld should be constantly alert for adverse effects or potentialnew hazards and reporting them to their National Centres.Manufacturers should also receive such information.International VigilanceThis principle is the basis for the WHO Programme for InternationalDrug Monitoring: all member countries have systemsin place which encourage healthcare personnel to record andreport adverse effects of drugs in their patients. These reportsare assessed locally and may lead to action within the country.Through membership of the WHO Programme one country canknow if similar reports are being made elsewhere. (TheEuropean Union also has its own collective international scheme.)Member countries send their reports to the Uppsala MonitoringCentre where they are processed, evaluated and entered into theWHO International Database. When there are several reportsof adverse reactions to a particulardrug this process may lead to theSIGNAL……is notice of an early concernor hypothesis about a possibledrug safety problem. DetectingSIGNALS is one of the primaryobjectives of member countriesof the WHO Programme forInternational Drug Monitoring.detection of a signal – a notice of a need for increased awarenessof a possible hazard communicated to member countries. Thishappens after preliminary evaluation and expert review, prior todetailed work on the ground by individual authorities.(Full details of this process of assessment are described in Part2. There are also details of the Bayesian ConfidencePropagation Neural Network (BCPNN) – a very sophisticatedautomated way of detecting if particular adverse reactionreports stand out from the background of the entire database.)Spontaneous ReportingOne of the problems with this voluntary system of ‘spontaneousreporting’, is that hard-pressed medical personnel don’t alwayssee it as a high priority. If the effects are not serious, they maynot get to know about them at all, and even if they are serious,they may not be recognised as the effect of drugs. Doctors mayalso worry that the adverse effects they report may be seen asthe result of their bad practice and leave them open to criticismor even litigation.Even so, spontaneous reports are a crucial element in the worldwideenterprise of pharmacovigilance and form the core of theWHO Database, which includes around three million reports,growing annually by more than 200,000. (See Part 2 for fulltechnical details.)Special MeasuresSome countries require spontaneous reporting by physicians bylaw. In most countries manufacturers are required to submitreports they receive from healthcare providers to the nationalauthority. Others have intensive, focused programmesconcentrating on new drugs, or on controversial drugs, or on the12

Watching…prescribing habits of groups of doctors,or involving pharmacists in reporting. Allof these generate potentially useful information.Such intensive schemes, however,tend to be the exception.There is some controversy about how farpatients should be involved in reportingadverse effects of drugs directly to theirNational Centres. There is no disagreementthat all patients should report adverseeffects to their doctors. Many peopleargue that there is a strong case for themto report direct to their national schemes.Their experiences may reflect differentconcerns from those of health professionals,and they may show up issues relating tocompliance. In particular, patients are betterable to give a picture of how the harmfrom the drug has affected them and theirlives.Watching the Worldthe UppsalaMonitoring CentreAfter the thalidomide disaster – beforewhich there were no national orinternational schemes for collectinginformation about emerging drug hazards– the World Health Organization (WHO)set up its Programme for InternationalDrug Monitoring at the same time as anumber of countries set up their ownschemes. Since 1978, responsibility formanaging this Programme has beencarried by the Uppsala MonitoringCentre (UMC) in Uppsala, Sweden.the UMC has achieved a great deal in itsmore than twenty years in collaborationwith the growing number of membercountries in the Programme (representingover one third of countries in the world),and with academic, scientific and medicalexperts and organisations throughoutthe world.There is no other official body in theworld which has a truly independent andglobal perspective on drug safety otherthan the WHO and its collaboratingcentre, the UMC. International harmonisationand standardisation are difficultto achieve without consensus. It is theWHO’s general mandate to do thiswork, and the record of achievement inthe field as a whole is now substantial,authoritative and widely-recognised.Full details of the UMC’s achievementsappear in Viewpoint Part 2.Go to: www.who-umc.orgPharmacovigilance in the 19 th CenturyThis raises some questions of practice(consistency and quality control forexample), but few in principle. Fewcountries have yet addressed this importantchallenge and established active patientparticipation.Over 150 years ago, on January 29, 1848,15-year-old Hannah Greener from Winlaton,north-east England, had a routine generalanaesthetic before treatment of aningrowing toenail. The anaestheticagent, chloroform, had onlybeen introduced into clinicalpractice a year earlier byJames Simpson, professorof midwifery at Edinburgh,since it produced less nauseaand vomiting than ether.Unfortunately, Hannah Greenerdied during the anaesthetic fromwhat was probably an episode of ventricularfibrillation. Because of the continuing concernsof the public and the profession about the safetyof anaesthesia, The Lancet set up a commission,which invited doctors in Britain and its coloniesto report anaesthesia-related deaths. Thesefindings were subsequently published in thejournal in 1893. Thus, the forerunner of aspontaneous reporting system forsuspected adverse drug reactions(ADRs) was established, at least fora time.Routledge PA. 150 years of pharmacovigilance.Lancet, 1998, 351:1200-01.For a tabular History of Pharmacovigilancefrom around 2000 BC (!) to the present day, seeStephens MDB, Talbot JC, Routledge PA, eds.Detection of New Adverse Drug Reactions, 4th ed.London, Macmillan, 1999: 2-4.13

Why do…Why do Adverse DrugReactions matter andhow do they happen?ADRs matter because pharmaceutical products and other substancestaken for medical purposes have the potential for harmingpatients, even killing them. (A very small number of peoplehave a serious or even fatal reaction to penicillin, for example.)ADRs happen for many reasons, some inevitable andunavoidable, some preventable.The inevitable reasons are:• The effects of any medical intervention cannot be predictedwith absolute certainty• There is no drug or medical intervention which will not havesome negative and undesirable effect on someone, somewhereat some time• Information about rare events may, by their very nature, notbe available until they happen.The preventable reasons include:• An error in diagnosing the disease• Prescription of the wrong drug for the disease• Prescription of the wrong dose of the right drug• Choice of the right drug for the disease, but maybe thewrong drug for the patient, because of a genetic or ethnicpredisposition, age, some other illness or medication, allergyor intolerance• Choice of an appropriate drug but without taking intoaccount the potentially harmful interactive effects with otherdrugs or substances being taken by the patient• The full specification, indications, contraindications and risksof the drug may not have been read or fully understood• The patient may not comply with the doctor’s advice or withthe manufacturer’s advice in the patient information leaflet• As long as people are choosing drugs and other substances fortheir own medication without professional advice, there maybe problems• The taking of many drugs (polypharmacy) or receivingtreatment from more than one source (polytherapy) cancontribute significantly to causing drug-related problems,particularly harmful drug interactions.The remedies for the preventable reasons areclear, if hugely challenging to achieve:• A higher priority in all medical training in the knowledge andskills associated with diagnosing and treating disease – includingtaking case-histories, diagnostic skills, pharmacology, and therecognition and reporting of adverse effects• Greater awareness by healthcare professionals and the generalpublic about the complexities and safety profiles of medicalinterventions• Much more effective communication and openness about thenature of drugs and their effects and the degree of uncertaintyassociated with them• Comprehensive public education and debate about the benefit,harm, effectiveness and risk of medical interventions andagreement about the balance of benefit, harm, effectivenessand risk which is acceptable, given that there will always besome uncertainty.• Wider discussion and education on the nature of risk in generaland its communication, and in the individual variables affectingperception and acceptance of risk.14

…and counterfeitingSpontaneous ReportingThis is the core data-generating systemof international pharmacovigilance,relying on healthcare professionals(and in some places consumers) toidentify and report any suspectedadverse drug reaction to their nationalpharmacovigilance centre or to themanufacturer.Among the system’s major weaknessesare under-reporting and variable qualityof reporting, though the figures varygreatly between countries and in relationto minor and serious ADRs.In the early 90s reporting rates wereestimated to be around 10% at best,often much lower*.*Fletcher AP. An Appraisal of SpontaneousAdverse Event Monitoring. Adverse DrugReaction Rev, 1992, II(4): 213-227.Package Inserts orLeafletsIn many countries, manufacturers arerequired by law to enclose informationfor patients about their products inthe package (this includes informationon the active drug substance itself aswell as the ‘excipients’ – the materialsincluded to bind the chemical into atablet, to stabilise it, and so on).While possible ‘side effects’ (adverseexperiences) of products must bementioned, there is usually littlediscussion of the probability of theiroccurrence, their seriousness orduration, though categories such as‘common’ or ‘rare’ are used.Medical ErrorDoctors and other healthcare providersmake mistakes. There is evidence thatexcessive and inappropriate prescriptionof drugs contributes substantially to theoccurrence of ADRs 1 and that hospitalpatients are particularly vulnerable tomedication errors 2 . The FDA (USregulatory body) has a reporting systemfor medical error 3The Institute for Safe Medication Practicesis an American non-profit organisationfor reporting medical errors. Its missionis: Educating the healthcare communityQuality Problemsand CounterfeitingThere are large volumes of drugs on theworld market which are either counterfeit(illegal copies) or sub-standard.Counterfeit drugs may also be substandard.Sub-standard drugs may contain littleor none of the labelled active ingredient.They may include other substances orinclude even contaminated or poisonousingredients. Some drugs are sold andused after their expiry dates and someare stored in conditions which damagethem.Spontaneous reporting can help exposesuch hazardous medicines when healthcarepersonnel are alert to unexpectedand apparently inexplicable adversereactions, or to lack of effect.These problems are relatively rare indeveloped countries where inspectionand quality control regimes are rigorous,but they are not unknown.about safe medication practices. Thereare contact organisations in severalcountries. Go to: www.ismp.org1 Leape LL et al. The nature of adverseevents in hospitalised patients: results of theHarvard Medical Practice Study II.New England Journal of Medicine, 1991,324:377-84.2 Bates DW et al; Patient risk factors foradverse drug reactions in hospitalisedpatients. Archives of Internal Medicine,1999, 59:2553-60.3 Medication Error Prevention Office ofPost-Marketing Drug Risk Assessment.Go to: www.nccmerp.orgGenerics or MultisourcePharmaceutical ProductsThese are copies or near-copies ofbranded drugs (usually drugs whosepatent protection period has elapsed)made and sold legally and subject tothe usual quality-testing procedures.Such products are usually intended tobe interchangeable with the originalproduct, but may be produced indifferent dosage forms and/or strengths.Widely available, they are favouredbecause they are usually much cheaperthan the original products. They mayor may not be sold under their ownbrand name.As with branded drugs, there areinstances of illegal manufacture anddistribution.15

CommunicationCommunication and Educationthe Uppsala Monitoring Centre has insistedfor some years now that among the crucialissues to be addressed is the achievementof open and effective communicationabout benefit, harm, effectiveness and riskand about drug safety issues in general.Technical and scientific issues clearlyremain of fundamental importance, butunless healthcare professionals, patients,the public at large and journalists reallyunderstand the issues, and are muchmore critical and discriminating in theirtreatment of medical information, therewill continue to be misunderstanding,mistrust, and crises which may damagepatients and public health. Such problemsmay also damage the legitimate interestsof pharmaceutical companies.The Erice Declaration* was an importantstatement of principle on these issuesresulting from an international conferencesponsored by the UMC and the EttoreMajorana Centre in Sicily in 1997.Among the many challenges identifiedthen and since are:• A greater willingness among regulatorsand manufacturers to show openness andtransparency in the communication ofthe information they have about drugs,especially in admitting uncertainty• A commitment to public education,including materials in school coursesabout the nature of medicine, the effectsof drugs and about being an intelligent,critical and empowered patient• More open and mature relationshipswith the media and the briefing andtraining of journalists on the scienceand its complexities• A commitment to include more extensivediscussion of and training in benefit,harm, effectiveness and risk and drugsafety issues (pharmacovigilance) in allmedical education• Efforts to ensure that all healthcare professionalsare alerted to the importanceof recognising and reporting ADRs andof encouraging their patients to do soas well.the UMC has strongly argued the casethat much greater imagination and professionalismis needed in the planning,design, composition and presentation ofmedical communications. ‘Brilliantscientists are not necessarily brilliantcommunicators’ is a truth not alwaysacknowledged by people who are expertin their own specialism, but may be onlyamateurs in the business of communication.It’s a huge challenge to compete forattention on equal terms in the crowded,noisy, modern world where communicatorsand their audiences are so verysophisticated. It’s a challenge thatrequires expert skills.*Go to: www.who-umc.org/publications/EriceTheGuardiansof DrugSafetyMost countries have a regulatory authority whichhas legal responsibility for controlling the use ofmedicines and other substances for humanconsumption (food, food supplements and foodadditives, for example).Various names…• Philippines: The Bureau of Food and Drugs• UK: Medicines and Healthcare productsRegulatory Agency• US: Food and Drug Administration• Australia: The Therapeutic GoodsAdministration• France: L’Agence du Médicament• Japan: The Pharmaceutical and FoodSafety Bureau.These organisations have a legal duty to protecttheir populations from harm, and usually carry outthe following statutory functions:• receive applications from manufacturersfor approval for new products• examine the data for product efficacy andsafety from clinical trials or other premarketingresearch• decide if the potential benefits outweigh theharms and if so, approve the product on thebasis of its risk profile and sometimes on thebasis of its cost• decide on the conditions for allowing theproduct on to the market and the informationwhich must be provided for doctors,pharmacists and patients• officially license the product for prescriptiononly (POM) or for sale over the counter (OTC)• keep watch over all products on the market• respond to any evidence of a change in aproduct’s safety profile or reports of problems• withdraw, modify or confirm a product’slicence after investigation of new concerns.Many also receive periodic safety update reports(PSURs) from manufacturers on the latest informationabout their products. The regulatoryauthorities usually advise their governments andcommunicate with medical and pharmaceuticalpersonnel, the media and the public on drugsafety matters.Often the same organisation manages the country’sdrug safety monitoring programme, including thereceipt and processing of spontaneous reports ofadverse drug reactions. There is a strong ethical andscientific case for these functions to be separated.An independent safety evaluation board is likely tohave a more objective and balanced view of theissues. Such a system is run in New Zealand, forexample.Most countries with drug safety programmesare members of the WHO International DrugMonitoring Programme.(Full details appear in Viewpoint Part 2.)16

Empowerment‘Patient Empowerment’Consumers and patients in many countriesare demanding a greater say in theirmedical treatment. This can only comeabout if there is a commitment to basiceducation in schools on health and medicalmatters, and if doctors and patientshave access to comprehensive, reliableinformation about treatment options.It requires doctors to take their patientsseriously as participants or collaboratorsin the choice and use of therapy (stillsomething of a radical proposal); andpatients to assert their right to as muchof a part in decision-making as they want.Some countries have excellent educationaland information programmes, as well asother printed and electronic resources.There is a growing movement worldwidefor greater lay involvement in medicalmatters. Patient liaison groups for professionalsocieties and health institutionsand patient representation or groups forgeneral or specific interests are increasinglycommon. These are sometimes independentpressure groups or officially-supportedactivities.Some examples of resources for patients:www.haiweb.org – Health Action International(HAI) is a non-profit, global network of health,development, consumer and other public interestgroups in more than 70 countries working for amore rational use of medicinal drugs. HAI representsthe interests of consumers in drug policyand believes that all drugs marketed should beacceptably safe, effective, affordable and meetreal medical needs. HAI also campaigns for bettercontrols on drug promotion and the provision ofbalanced, independent information for prescribersand consumers.Grant R, Which? Medicine, ConsumersAssociation (UK), 2000Patient FASS Farmacevtiska Specialiteter i SverigeA version of the manufacturers’ organisation’s(LIF) drug reference list produced specially forpatients. Available in printed booklet or on theinternet: www.fass.seSIGNAL, occasional newsletter produced by theBureau of Food and Drugs, The Philippineswww.dipex.org – a database of patientexperiences of medical treatmentwww.patientsorganizations.org – an internationaldatabase of patient organisationswww.consumersinternational.org– international organisation working for theinterests of consumerswww.quackwatch.com – a fascinating andprovocative (if occasionally controversial) accountof a wide range of medical matterswww.usp.org/drugInformation – Wide-rangingdrug information from the United StatesPharmacopeia (USP), including drugs on the market,for public review and commentwww.nlm.nih.gov/portals/public.html– Easily accessed information about 11,000 drugsfrom the USP (see previous item)ChallengingissuesThe impact of global pharmaceuticalactivity and consumption on world issuesis huge – economic, political, social,ethical, as well as medical.There is the suggestion that ‘…tradeagreements reinforce justifications forcommercial secrecy to the detriment ofscientific openness and drug regulation,’and that ‘…Lack of access to essential 1 Stolley PD, Laporte JR. The Public Health,drugs and vaccines because of economic the University, and Pharmacology. In: Stromfactors raises human rights issues.’ 1 BL, ed. Pharmacoepidemiology, 3rd ed.Chichester, Wiley, 2000:82-83.Recent figures from WHO indicate that2 as above, page 81.one third of the world’s population doesnot have access to essential drugs.Pharmaceutical consumption in the topten countries (including 17.5% of totalworld population) in the year ending 30June, 1999 (amounting to 190 billiondollars) was around 60% of total worldconsumption in that year (amounting to315 billion dollars). 217

QuestionsQuestionsandAnswersAfter covering so much ground in this booklet, here again arethe questions from the opening page, this time with some ofthe challenges to which we should be alerted and the action weneed to take:Has the disease been correctly diagnosed?• The need for up-to-date refined and sophisticateddiagnostic skills• Increased awareness that symptoms may be caused by adversereactions to drugs or other substances already being taken,as well as by disease.Has the right dose of the right strength of the right formulationof the right drug been prescribed?• Provision of easy access to clear and comprehensiveinformation about the drug and its use and about possiblealternative therapies, for the prescriber and the patient.What are the risks of the treatment producing an adversedrug reaction (ADR)?• Provision of comprehensive, accessible, up-to-date informationabout all known ADRs, the risk of their occurring generallyand for this particular patient, their potential seriousnessand duration.What is the potential seriousness and duration of possibleharmful effects?• Informed discussion with the patient about their particularview of the potential benefit and harm in relation toeffectiveness and risk for them.Is the patient taking anything else which might interact badlywith the drug or prevent its working at all?• Public education in the way drugs work and on the way theyinteract with many other medical and non-medical substances• Patient awareness of the critical nature of issues which maynot seem immediately relevant to the present consultation:for example, patients may not regard all drugs they aretaking as drugs, and may therefore not mention such productsas aspirin, oral contraceptives, vitamins, herbal remedies.Does the patient have any medical or genetic or allergiccondition which might cause a bad reaction to the drug?• Training in the expert and thorough taking of case-historiesand in effective interaction with patients• Continuity of care or, at least, excellent communicationsbetween healthcare providers about their shared patientsIs the manufacturing source of the drug safe and reliable?• Universal requirement for adherence to WHO GoodManufacturing Practice (GMP), including strict inspectionand quality control by manufacturers and regulators (this is aserious problem in some developing countries)• Reliable and conscientious reporting by health providers andpatients of occasions where drugs cause adverse reactions, ordo not work at all (the drug may be contaminated or containno active substance).Does the patient understand the instructions and will they befollowed exactly (the issue of compliance)?• Much more sophisticated communications skills in healthcareproviders (and probably more time)• Much greater understanding among patients about howdrugs work and the necessity (for example) of completing acourse of treatment even if symptoms appear to have gone.18

QualityAssessing benefit and harm (as opposedto effectiveness and risk) is both a scientificand sociological pursuit.Scientists cannot judge how all patients,or some patients – or this patient – willassess the potential benefit and potentialharm of a particular therapy. Onlypatients can tell us what they want, andhow it contributes to their quality of life.Commonly, the term ‘benefit’ has beendefined only by scientists and usuallyrefers only to technical, therapeuticeffectiveness and not to emotional, socialor psychological benefits which may beequally or more important.Quality of LifeA patient with terminal illness may bewilling to tolerate radical and unpleasanttherapy to prolong life – or may opt for alife-enhancing therapy which may givestrength and energy for a short time.There are equally complex issues to beaddressed for those with chronic diseasewhich does not threaten life.A patient with a minor ailment may beunwilling to take the risk of adverse effectsof a drug that could be equal to or moreserious than the original illness, orconversely, the patient may judge thatthe illness is sufficiently troubling to takethe risk.Quality of life issues are intensely personaland individual – and no one but patientscan say what matters to them.Signal… is an early alert of a possible drug safety hazard. Detecting SIGNALS isone of the primary objectives of member countries of the WHO Programmefor International Drug Monitoring19

The CurrentState of Play• The science of pharmacovigilance isrelatively immature and is only nowbeginning to develop the theory andtools to have a significant impact onpatient care and public health• Since thalidomide, there has been nocomparable drug disaster. Drugs causingserious harm have been identified andaction has been taken before widespreaddamage occurred (examples includepractolol, bromfenac and troglitazone).• There has been little substantial, scientificevaluation of the outcomes andeffects of pharmacovigilance worldwide• Where there has been assessment, ithas been on the basis of looking atregulatory action (number of drugwith-drawals or label/package insertchanges, for example) rather than onthe ultimate impact on prescribinghabits, rational drug use, patienttreatment and public health• Regulatory action is only an intermediategoal of pharmacovigilance, though it hassometimes been seen as the ultimate goal• The evidence for the expected impactand outcomes from withdrawals andother regulatory action are not readilyavailable for public scrutiny, if at all• Assessment of the effect of issuingwarnings about particular drugs (e.g.‘Dear Doctor’ letters and other methods)suggests that they have little effect, andmuch more imaginative communicationsapproaches to change prescribing habitsare required• Studies on ADRs and hospital admissionsover many years suggest little change inrates of illness and death attributable todrug complications in spite of warningsand advice• There is some evidence that the wisdomof pharmacovigilance is influencingmedical education, but it is still a verylow priority in most professional healthcurricula• Patients in some parts of the world arebecoming more demanding andassertive and less willing simply to trusteverything they are told.The Role of the UMC• ‘Never miss a signal’ is a goal for theinternational collaboration of membercountries in the Programme, supportedby the UMC• the UMC has drawn attention to mattersof concern which have arisen fromexamination of the international data,but its primary role is to facilitate thepharmacovigilance of member countriesby the provision of information andtools• the UMC is not directly in control ofultimate end-points of action withinthe Programme as individual countriesmake their own decisions on the basisof information available• the UMC has concentrated on theweakest elements in the science andsystems of pharmacovigilance and providedsignificant development• The Bayesian Confidence PropagationNeural Network tool (BCPNN), developedby the UMC, is a great advancewhich provides one of the best toolsavailable internationally for signaldetection which has been assessed foreffectiveness. (See Part 2, for a detaileddescription of this process.)• the UMC has raised and promoteddiscussion of the issues of benefit/effectiveness, harm/risk, essential to theachievement of the higher goals ofpharmacovigilance• the UMC has raised the questionabout the essence of the meaning ofpharmacovigilance in the worldwidemedical community (‘What are themessages?’) and the challenge of effectivecommunication of them (‘How arethe messages to be conveyed?’) to allaudiences• the UMC’s concern with the centralscientific issues of pharmacovigilanceand the ultimate effects on patient careand public health may not fit easilywith the way pharmacovigilance isgoing internationally: there is anincreasing emphasis on regulatoryaction, rather than on open and reflectivescientific progress, learning fromexperience and rational use of drugs• the UMC has had a significant impacton the thinking and practice of the staffof the National Centres of membercountries, on the growth of pharmacovigilanceactivities round the world,and on the establishment of newNational Centres• the UMC’s ‘success’ must be judgedlargely by the effectiveness of the drugsafety activities of the community ofNational Centres and on their impacton patient therapy and public health intheir own countries. Research in thisarea remains an important priority.20

Herbals…Herbalsand TraditionalMedicinesWhile enormous quantities of modernmedicines (known as allopathic medicines)are consumed worldwide, there arecertainly much greater quantities ofherbals (and traditional medicines andmodern phytotherapeutic and homeopathicmedicines) being taken by largenumbers of people in every country.In many developing countries there arefar more traditional practitioners thanmedically qualified doctors. In thesecountries the great majority of thepopulation rely largely on traditionalremedies, since they are relatively cheapand readily available.In developed countries, where medicalservices are comparatively comprehensive,the popularity of non-allopathic remedieshas soared in recent years.Why Monitor Herbals?• Few traditional remedies are todaysubject to any regulation, inspection orquality-control in their collection,production or distribution.• The ingredients of traditional remediesare sometimes uncertain. the UMC istaking a major role in serious work beingdone to make it possible to classify theirsources and standardise references toplant names and parts. (See Herbals inViewpoint Part 2.)Traditional practitioners learn their professionthrough apprentice systems andnot through text books. Little is knownby health professionals about this processand the knowledge it imparts. Very littleis known about the interactions betweenallopathic and herbal-based medicineswhether traditional or modern.Monitoring herbals in the same way asallopathic remedies is beneficial both tothe populations of developing countriesthat depend on traditional remedies fortheir health care, and to developedcountries where herbal remedies are amore and more important element ofmodern life.Another aim of promoting the monitoringof herbals it to make the two sciencesmore mutually understood and accepted.The widening arena of pharmacovigilancePharmacovigilance is changing! In the past it has been seen asa relatively limited – though important – technical activityconcerned with the identification of adverse drug reactionsfrom pharmaceutical products. Its uses have been more or lessconfined to regulatory deliberations and decisions.Increasingly, it is now seen as the starting point for theconsideration of larger and more radical questions:• the benefit, harm, effectiveness and risk of medicinal productsas they affect individual patients and public health• the safety of all substances used in medical or alternativepractice – herbals, vaccines, blood products and so on• the rational use of drugs in collaborative relationshipswith patients• the communication of complex issues among healthcareprofessions and with the media, patients and the publicat large.21

GlossaryThe following list contains the majority of words used in specialised ways inpharmcovigilance and which appear in the text in this publicationWordMeaningAbsolute risk The probability of an event affecting members of a particular population (e.g. 1 in 1,000)Adverse drug reaction (ADR)AllopathyAssociationAttributable riskBenefitCausal relationshipNegative effects or lack of effect, from taking a drug at normal doseThe treatment of disease by conventional (Western) means, usually in opposition to the disease(allo- = other, different, opposite). Compare Homeopathy, belowEvents associated in time but not necessarily linked as cause and effectThe difference in the probability of an event happening, directly attributable to a drug or other variableThe proven therapeutic good of a product; should also include the patient’s subjectiveassessment of its effectsWhere there is a cause-effect relationship between two eventsCommon In pharmacovigilance, an event with a probability between 1 in 100 and 1 in 10ComplianceControl groupEffectivenessEfficacyEpidemiologyEventExcipientsGenericsHarmHomeopathyMember countriesNational CentresOver the counter (OTC)PharmacoepidemiologyPharmacologyPharmacovigilancePhocomeliaPhytotherapyPlaceboPre-marketingPost-marketingPrescription only medicine (POM)ProphylaxisFaithful adherence by the patient to the prescriber’s instructionsThe comparison group in drug-trials not being given the studied drugThe probability of the drug working as expected in the clinical setting (opposite to its risk of harm)The intrinsic capacity of the drug to work in ideal experimental circumstancesThe study of disease in large populationsA specific, identifiable happening or occurrence, e.g. the taking of a drug; the experience of an ADRAll materials included to make a pharmaceutical formulation (e.g. a tablet) except the activedrug substanceCopies or near-copies of branded drugsThe nature and extent of the actual damage that could be causedThe treatment of disease by means with similar effects to the disease. Compare Allopathy, aboveCountries which comply with the criteria for, and have joined the WHO Programme for InternationalDrug MonitoringOrganisations recognised by government to represent their country in the WHO Programmefor International Drug MonitoringA drug licensed for retail sale through pharmacies or other outlets, without a prescriptionBranch of epidemiology (see above) dealing with the effects of drugs in large populationsStudy of the uses, effects and modes of action of drugsThe science of collecting, monitoring, researching, assessing and evaluating information fromhealthcare providers and patients on the adverse effects of medicines, biological products, herbalsand traditional medicinesCharacteristic deformity caused by exposure to thalidomide in the womb, also very rarely occurringspontaneously. Means: limbs like a sealWestern-style, scientific treatment with plant-extracts or materialsAn inactive substance (often called a sugar pill) given to a group being studied to compare resultswith the effects of an active drugThe stage before a drug is available for prescription or sale to the publicThe stage when a drug is generally available on the marketA drug licensed only for prescriptionPrevention or protectionRare In pharmacovigilance, an event with a probability between 1 in 10,000 and 1 in 1,000Regulatory authorityRational drug useReference riskRelative riskRiskSignalSpontaneous reportingThalidomideThe legal authority in any country with the responsibility for regulating all matters relating to drugsA visionary concept implying the achievement of rational, intelligent, critical prescribing and use of drugsThe probability of an event happening in the non-exposed population (‘background’ risk)A comparison of the probability of an event happening for the exposed and non-exposed population,expressed as a ratioThe probability of harm being caused; the probability (chance, odds) of an occurrenceNotice of an early concern or hypothesis about a possible drug safety problemThe core data-generating system of international pharmacovigilance, relying on healthcareprofessionals (and in some places consumers) to identify and report any suspected adverse drugreaction to their national pharmacovigilance centre or to the manufacturerDrug prescribed in 1950s as mild sleeping pill and remedy for morning-sickness for pregnant women.Led to serious birth defects. Returning to favour as a treatment for leprosy.22

Watching the Worldthe Uppsala Monitoring CentreGreetings from Ralph Edwards,Director of the UMCI do hope you have found this booklet interesting, stimulating– and enjoyable!Increasingly at the UMC, we believe our job is not just todevelop technical leadership in worldwide pharmacovigilance,but also to provide a forum for the major issues and controversieswhich intelligent pharmacovigilance will always raise. This isthe first time we’ve put these issues into print for a wide,general audience.The science – however good – is no use to anybody if it is notavailable, understood, and used by everyone concerned withsafer use of medicines and rational clinical practice. Effectiveeducation and communication are critical to these goals.Viewpoint is one of the UMC’s contributions toachieving them.We hope these booklets will:• Stimulate debate• Educate• Widen the audience concerned about the issues• Provide useful technical information about the UMC’sactivities and about the science of pharmacovigilance• Promote the interests of patient care and public healthworldwideNow you’ve reached the end – please let ushave your opinion of this first part ofViewpoint. We’re very keen to have yourfeedback so we can do better next time.Email: info@who-umc.org, orFax: Cecilia Biriell on +46 18 65 60 80the UMC is here to provide information and service: please tellus how we can help you or provide you with the resources youneed. If you haven’t seen the companion volume, ViewpointPart 2, please contact us and ask for a copy. And do please tellus what you think of the booklets.Best wishes from the whole team in Uppsala!Ralph Edwards

The companion booklet, Viewpoint Part 2,contains the following material:A full description of the WHO Programme for International Drug Monitoring,and detailed scientific and technical accounts of• Adverse Drug Reaction Reporting Systems, Evaluation and Quality Control(including the Bayesian Confidence Propagation Neural Network for signaldetection)• Core Products and Services (including the WHO Drug Dictionary andmuch else)• Publications• Collaborations• Communications• Issues in Pharmacovigilance• Training• Consumer and Patient Groups• Bibliography of UMC academic publications– and considerably more, including a list of acronyms,a specific glossary and scientific definitions.Copies obtainable from the UMC.How to find out more:The website of the UMC – www.who-umc.org – contains Viewpoint Parts 1 and 2(including summaries in English, French and Spanish) and much more, includinglinks to related sites of interest.For more copies of this booklet or of the companion volume, or summary versionsin English, French or Spanish or for any other enquiries or information, pleasecontact us:Fax: +46 18 65 60 80Email: info@who-umc.orgContact from you will be very welcome!Acknowledgementsthe UMC acknowledges with thanks the advice and support of many friendsand colleagues in the preparation of Viewpoint, in particular:Tom Bell, Julie Bowdler, Ian Cockburn, Arnold Gordon, Andrew Herxheimer,Kenneth and Catherine Hartigan-Go, Ana-Maria Côrrea Nunes, Alejandro Maria GoyretSacarelo, Nermine Zejnullahu, who read and commented on early drafts.Photo Credits: Geoffrey Bowring, Bruce Hugman, Cecilia Biriell, Cancer Relief India, PreviewWHO Collaborating Centrefor International Drug MonitoringStora Torget 3, S-753 20 Uppsala. SwedenTel +46 18 65 60 60. Fax +46 18 65 60 80E-mail: info@who-umc.orgWebsite: www.who-umc.orgViewpoint edited by Bruce Hugman, (Consultant to the UMC) (+44 7770 725354);Project Co-ordinator Cecilia Biriell (UMC); designed and typeset by Vajer [wire], Uppsala(+46 18 10 94 01); printed in Sweden by TK Uppsala.Viewpoint © the Uppsala Monitoring Centre 2002Second printing 2005