Beginning October 1, 1998, chlordane - a chemical used mainly by pest control companies for the treatment of termites will be banned according to the Malaysian Pesticide Board recently. This move is indeed very appropriate since the US Environmental Protection Agency has done so ten years ago in 1988. The substance has been known for it hazardous effects both short-term and long-term. The former included gastrointestinal and neurological problems like tremors and convulsions in humans.
The long-term effects also involved other organs: the heart, the lungs and even the blood. Chronic neurotoxic effects associated with low-level exposures to the chlordane were further substantiated in a study in 1995 on protracted neurotoxicity from chlordane sprayed to kill termites. The deficits identified included that of balance, reaction time, and verbal recall. Studies too have confirmed that in animals the chemicals can cause reduced fertility and caused neurological defects in their offsprings.
In Malaysia, the choice for using chlordane is said to be because of its relative cost as compared to other available alternatives. Also, it is perceived as effective since its residue can persist in the ground for up to 40 years once it is pumped in. On the contrary this is in fact one of the major setback of chlordane because of the risk that Malaysians could be exposed to due its persistent nature in the environment. It is therefore high time that such chemicals be removed from our market as soon as possible.
The ban on the manufacture and importation of chlordane however has also raised some larger questions. Foremost, chlordane belongs to a group of chemicals generally known as "persistent organic pollutants" or POPs for short. They include similar organochlorine compounds like DDT, PCBs, furans, heptachlor, aldrin, dieldrin and endrin. Some of these are still common found in Malaysia. Many of them are used in or arise from industry, agriculture and disease vector control. They may also be created unintentionally, as by-products. As such all of them can result in environmental health risks. Because of their persistent nature, over a period of time, their concentrations can increase to levels that eventually effect health.
Dangers of other POPs
The best known example is perhaps DDT, which has been widely used for many years for vector control around the world. It has a low acute toxicity in humans and for a while was regarded as 'safe'. However, it is now recognised that DDT has a number of long-term effects including acting as "endocrine disruptor" namely in mimicking steroid hormones in the human body. Moreover, the reports of high concentrations of DDT found in human breast milk especially in developing countries point to the possibility of environmental accumulation of DDT. One prospective study based on the New York University Women's Health Study in fact, showed a significant association between body stores of the DDT metabolite, DDE, and breast cancer.
On the other hand, eldrin, another POP, is even more hazardous. As a comparison, it is reported to be between two to four times more toxic than DDT (LD 50: 16-43 mg/kg in rats), despite endrin being more readily meta-bolised. Food contamination with endrin has caused several clusters of illness worldwide especially with regard to poisoning in children. But these are often overlooked because the symptoms resembles those of encephilitis, making the cause not immediately apparent.
Yet another group of great concern is the polychlorinated biphenyls (PCBs). They have been around since 1929 but was banned more that 20 years ago in the US. PCBs are made up of more than 200 related compounds which because of their many ideal characteristics are used in a number of industrial applications, especially as insulators. Their wide acceptance have "insulated" them from being made a focus of potential health and environmental problems.
The extent to which PCBs can affect us today cannot be overemphasied since at time of their discovery as environmental and health hazards, they had been produced and used extensively for more than 3 decades.
Like most POPs, PCBs too can accumulate in the fatty tissue, and over the years it becomes clear that PCBs have been detected in food samples from all over the world. They can enter the food chains and disrupted them. The higher the level of the food chain, the greater the concentration of PCBs. Some have been passed on to eggs (for birds and fishes) as well as milk (for mammals), and eventually humans. Indeed, PCBs can be traced to humans by consuming such contaminated food, and through breast milk in the case of infants. One report submitted to the UK Department of Health stated the "[b]reast fed infants are receiving up to 17 times the tolerable amounts of dioxins and polychlorinated biphenyls (PCBs)."
PCBs and IQ
One of the most alarming exposure effects of PCBs, however is the lowering of IQ, a subtle and devastating impact. It was recently confirmed that children exposed to the low levels of PCBs in the womb grow up with low IQs, poor reading comprehension, attention deficit as well as memory problems. Even at the age of 11, maternal exposures to PCBs were correlated with lower overall IQ and lower verbal IQ score. About 11 percent of the children whose mothers has highest exposures now have IQs 6.2 points lower than average. Other researchers suggested that the mechanism of harm of PCB involves with interference with the thyroid hormones, which are essential for development of the brain.
Children exposed to PCBs in the womb at levels regarded as "background levels" in the US have also been reported to experience loss of muscle tone, poor reflexes at birth, delays in psychomotor development at ages of 6 and 12 months, and diminished visual recognition memory at 7 months. Others have reported of findings like "balky, uncooperative behaviour" suspected to be linked to exposure of higher levels of PCBs. All these invariably are related to the presence of PCBs in the environment - be it in storage, landfills, in sediment of lakes, rivers, or even oceans - apart of the larger proportion that are in use, estimated at 70 percent of the total. Given all these findings, it is therefore not suprising that a ban was imposed on PCBs by the US Congress - outlawing the manufacture, sale and distribution - as early as 1976, except in "totally enclosed" systems. Even then, although their use in heat transfer and hydraulic systems can be regarded as "closed," there is always the risk of leakage and exposure.
The question of safety
Thus, while the banning of chlordane can be seen as a step in the right direction, it by not means the only substance of concern. Many more should follow suit in the immediate future. We must continue to weed out as many POPs as possible in the shortest time frame possible until they no longer pose potential risks to the population. In fact, in a recent WHO report (1997) as part of the review five years after the Earth Summit, considerable attention has recently been focused on POPs (see box). The report commented that the use of such substances cannot be considered sustainable. Increasing evidence of the long-range transport in the environment of these substances and the consequent threats they pose to the whole globe, has prompted the international community to call for urgent global action to reduce and eliminate releases and emissions of these chemicals.
Among the twelve POPs under initial consideration for international action, DDT is the only insecticide still in use for public health purposes, notably vector control. DDT has made major impact to the eradication, or virtual eradication of malaria from a number of countries, including Malaysia. Even then the use has declined following development of vector-resistance, reduction in its global production and adverse recent findings.
In other words, the POPs is fast losing its 'popularity' and Malaysians should be spared of any potential hazardous that could arise from being accessible to such hazardous substances. The only way that this can happen for certain is by eliminating all of them from our mwrektt as soon as possible.
The Environmental and health dangers of POPs
POPs "persistant organis pollutants" are organic compounds that have long half-lives in the environment and undergo slow physical, chemical, and biological degradation. They are able to pass through ecosystems because of their high vapour pressure and can travel great distance, both locally and globally. Examples of POPs are aldrin, chlordane, DDT, dieldrin, eldrin, furans, heptachlor and polychlorinated biphenyls (PCBs). All of them are organochlorine compounds used as mainly as insectidices.
Most presist for a very long time in the environment. POPs have high lipid solubility and therefore bioaccumulate in the fatty tissues of living organisms. They too have long half-lives in the body and can be measured several months to several years after substantial exposure. These characteristics mean that they can pose a special threat to the environment and human health.
They pose a special risk to human health and the enviroment since they mimic the function of steroid compounds such as hormones potentially leading to disruption of the endocrine system.
Human exposures to POPs occurs via diet, occupation, accidents and the indoor environment, particularly in countries where POPs are used in tropical agriculture. Of late even the World Wildlife Fund (WWF) has expressed concern over the impact of POPs in the environment of animals namely the avian species. This could further implicate exposure to humans.
Apart from its use, the stockpiling of unwanted POPs is also significant cause for concern worldwide. In the 50th World Health Assembly (May 5-14, 1997), in addition to the mainstream resolution on combating infectious and communicable diseases, international action was demanded on POPs, such as PCPs and DDT.N
Source: IPCS, 1995; IFCS, 1996; Lancet, May 17, 1997, p.1460.
PRN CONSULT
In conjunction with International Pharmacovigilance Seminar, 12-13 October 1998, Kuala Lumpur
Overview on
Adverse Drug Reactions
by Rahmat Awang PharmD
Drug therapy has contributed significantly to the success stories of managing human illnesses. However, its use is not without risk. They are known to contribute many adverse reactions which have caused significant morbidity and mortality. Most adverse drug reactions (ADR) are predictable and preventable while the remaining few are unpredictable but may posed very serious consequence.
This article aims to promote awareness among health care providers on the issues relating to ADR. It is hoped that health care providers would maintain continuous vigilance and always take time to consider the potential risks of a drug against its benefit whenever a drug therapy is to be initiated.
What is an ADR?
The World Health Organization has defined ADR as any noxious, unintended, and undesired effect of a drug, which occur at doses used in humans for prophylaxis, diagnosis or therapy. This definition excludes therapeutic failures, intentional and accidental poisoning (ie, overdose), and drug abuse. It also does not include adverse events due to errors in drug administration or non-compliance (taking more or less of a drug than the prescribed amount).
How frequent does ADR occur?
The exact incidence/prevalence of ADR is not known despite various attemptscarried out by numerous researchers. At best, these rates are only estimates and they vary based on the surveillance methodologies employed, types of patient population studied and criterias adopted to determine causation. However, it is accepted that ADR increase hospital admission rates, increase morbidity and mortality, and significantly increase health care cost.
Generally, the incidence has been estimated to range between 1 to 28%. Hospital admissions due to ADR ranges from 2 to 5%. Agents most often implicated include antiarrhythmics, antibiotics, anticoagulants, anticonvul-sants, antineoplastic agents, aspirin-containing compounds, corticosteroids, digitalis glycosides, diuretics, and psychotropic agents. Among the in-patients, between 4.8 to 35% developed ADR while in the hospitals; with about 0.31% may die due to it. For the newly marketed drugs, 2 to 41% of ADR occurs in the outpatient setting.
Why ADR occur despite extensive clinical trials done in the premarketing phase?
Drugs that are approved for use had undergone extensive preapproval testing to ensure safety and efficacy.
Despite the extensive studies carried out, many of the serious ADR cases are seen after it had been approved for use. Table 1 provides a list of some of the important ADR that were detected and actions taken on them.
Table 1 Some important ADR reported (1937-1991)
| Year | Drug | Nature of the ADR | ADR Action Taken |
| 1937 | Sulphanilamide | Liver damage | Solvent changed |
| 1954 | Diododiethyltin | Cerebral edema | Drug was withdrawn from the market |
| 1961 | Thalidomide | Congenital malformations | Drug was withdrawn from the market |
| 1966 | Chloramphenicol | Blood dyscrasias | Its use has been restricted |
| 1975 | Clioquinol | Subacute myelo-optic neuropathy | Drug withdrawn from the market |
| 1987 | Practolol | Oculomucocutaneous syndrome | Its use has been restricted |
| 1982 | Benoxaprofen | Liver damage | Drug was withdrawn from the market |
| 1983 | Etomidate | Adrenal suppression | Its use has been restricted |
| 1983 | Zimeldine | Hypersensitivity | Drug was withdrawn from the market |
| 1983 | Zomepirac | Anaphylaxis | Drug was withdrawn from the market |
| 1984 | Indoprofen | Gastrointestinal bleeding and perforation | Drug was withdrawn from the market |
| 1984 | Osmosin | Gastrointestinal ulceration and perforation | Drug was withdrawn from the market |
| 1984 | Phenylbutazone | Blood dyscrasias | Its use has been restricted |
| 1986 | Aspirin | Reye's syndrome (children) | Its use has been restricted |
| 1986 | Nomifensine | Hemolytic anemia | Drug was withdrawn from the market |
| 1986 | Tocainide | Neutropenia | Its use has been restricted |
| 1987 | Suprofen | Renal impairment | Drug was withdrawn from the market |
| 1988 | Spironolactone | Animal carcinomas | Its use has been restricted |
| 1989 | Flecainide | Cardiac arrhythmias | Its use has been restricted |
| 1990 | L-Tryptophan | Eosinophilia-myalgia and syndrome | Drug was withdrawn from foodstuffs |
| 1990 | Metipranolol 0.6% eyedrops | Anterior uveitis | Drug was withdrawn from the market |
| 1990 | Xamoterol Worse | Heart failure in some patients | Its use has been restricted |
| 1991 | Noscapine | Gene toxicity | Drug was withdrawn from the market |
| 1991 | Terodiline | Cardiac arrhythmias | Drug was withdrawn from the market |
Source: Modified from Oxford Textbook of Clinical Pharmacology and Drug Therapy; Tokyo:Oxford,1992
As mentioned earlier, all potential drug compounds have to undergo both preclinical and premarketing studies before they are approved for use in human. Preclinical studies are used to identify promising compounds for marketing. However, most of their important effects cannot be evaluated based on animal studies alone. Thus, this is followed by premarketing studies which consisted of three phases. Generally, phase I studies may passed up to about 70% of compounds which is followed by a phase II, which may passed about 30% of compounds. Finally about 5 to 30% of these compounds would have undergone complete testing of the phase III studies but only about 5-6% of the compounds may passed the stringent tests before they go into the market. The types of studies and its purpose, carried out in these three phases are listed in Table 2.
Table 2 Premarketing studies: Various clinical study phases (I-III) and its description
| Phase I | |
| Purpose: | Determination of the compound safety profile and its safe dosage range |
| Type of studies: | Pharmacokinetic and pharmacodynamic |
| Type of study populations: | Normal, healthy volunteers involving patients between 20 and 100 |
| Type of study design: | Single dose escalation or short-term multiple doses, inpatients. |
| Phase II | |
| Purpose: | Assessing efficacy of the compound; Determination of the optimum dose, and ADR profile |
| Type of studies: | Controlled efficacy studies; dose ranging or dose response |
| Type of study populations: | Number of patients involved in the study ranges between 50 and 500. |
| Type of study design: | Short-term; randomised placebo-controlled or dose comparison; double blind studies |
| Phase III | |
| Purpose: | Determination of the compound's efficacy and safety profile; including during long-term drug use |
| Type of studies: | Placebo, dose or comparator controlled |
| Type of study populations: | Number of patients may be as high as 3,000 patients |
| Type of study design: | Double-blind, multi-centre; multiple end-point |
From the premarketing studies carried out, only relatively small numbers of patients with as low as several hundred and seldom exceed a few thousand subjects were involved. This number may be too small to detect many of the less common but serious ADR. Based on the rule of 3 (Table 3), a sufficiently large number of subjects is required, which is at least 3 times the frequency of the ADR. Thus, if an ADR is suspected to occur in one out of 10,000 subjects, 30,000 subjects need to be observed in order to be 95% likely of detecting the ADR. Such a large sample size could not be gathered in the studies carried out in the pre-marketing phase thus making it less likely to be effective in detecting rare but important ADR.
In addition to the relatively small sample size, these studies have other limitations such as with respect to short duration of therapy (mostly, less than 2 years of follow-up), highly screened volunteers or homogenous groups of patients with uncomplicated diseases, limited treatment with other concurrent medications and exclusion of children, pregnant women and the elderly.
As a result, phase IV studies that addresses the limitations of phase III clinical trials have been recommended and introduced to ensure the long-term safety of the approved drugs (Table 4).
| Phase IV | |
| Purpose: | Postmarketing studies, evaluation of new indications and formulations for product; evaluation of long-term safety of product through spontaneous ADR reporting |
| Type of studies: | Long-term safety and efficacy surveillance, pharmacoeconomic studies, drug interaction |
| Type of study populations: | Patients; normal healthy volunteers |
| Type of study design: | Double-blind, single centre or multi-centre; placebo-controlled or dose comparison |
What are the types of ADR known to us and how can they occur?
All ADR are not of the same kind and there is no universal system of classifying them. One approach is to classify them type A- or type B- ADR. Between these, type A-ADR are predictable in nature. The reaction is usually an extension of the pharmacological action of the drug, quantitatively normal but augmented. Such reactions may be related to the primary as well as the secondary actions of the drug. These ADR are relatively common contributing to approximately 80% of the known ADR. They are usually identified before the drug has been marketed. The ADR are generally not very serious and rarely life-threatening. In addition, the reaction is dose-dependent and most of them can be prevented or may resolve following reduction in the dose.
A number of explanations have been put forward to explain type A-ADR. These include factors that relate to the formulation of the drug product such as particle size, the nature and quantity of excipients which can affect the release characteristics. A good example is the incidence of gastrointestinal bleeding and haemorrhage from the rate-controlled preparation of indomethacin (Osmosin). Another explanation relates to the changes in the pharmacokinetic properties of the drug due to alteration in the absorption, distribution, metabolism and elimination of drugs. Such alterations can result in the rise of drug blood concentration resulting in a corresponding change in the pharmacological effects. Another explanation relates to the pharmacodynamics of drug effect whereby there is an increased sensitivity of target organs or tissues.
Type B-ADR on the other hand are rare but bizarre reactions that is considered unpredictable or unexpected when it is based on the known pharmacological effects of a drug. The reactions are generally not related to the dose administered and can be serious enough to cause death. Idiosyncratic reactions, allergic (hypersensitivity) or pseudo-allergic reactions as well as anaphylactic reactions are among the type B-ADR known to man.
Type B-ADR can result from abnormalities in absorption, distribution, metabolism or elimination or due to genetic abnormalities that lead to abnormal and unpredictable responses to drugs. It can also be the result of an immunological response to the drug. Table 5 provides a list of examples of type B-ADR based on the above mechanism.
Deficiencies in certain detoxification mechanisms Deficiency in microsomal epoxide hydrolase of fetus may increase the risk for teratogenic effects of phenytoin as well as adverse reactions to carbamazepine Genetic abnormalities leading to abnormal and unpredictable responses to drugs
Immunological responses due to the drug
|
In addition to this, type B-ADR can be the effect of the formulation itself. For example, the excipients found in the pharmaceutical formulation can contain colouring agents, preservatives and antioxidants. Though they are generally considered inert, pharmaceutically inactive and nontoxic, adverse reactions have been reported with tartrazine, FD&C yellow No.5, mercurial antiseptics (thiomersal), and sodium metabisulfite. These adverse reactions tend to be allergic in nature.
Who are at risk of developing ADR?
All drugs have both therapeutic and adverse effects. Potentially, anybody is at risk of developing an ADR when exposed to a drug. However, the likelihood of experiencing ADR may depend on a number of factors. Generally, it is quite well accepted that the more drugs being taken by the patient, the higher will be the risk of developing ADR. This is especially true when the consumed drug has a low therapeutic index or interacts among themselves. In addition to this, patient- and disease-related factors may influence the likelihood of ADR occurrence. The following are known to influence the risk of ADR.
| Age
More frequent ADR is seen in elderly patients compared to younger patients. This may be caused by compromised organ function that is responsible for drug elimination or could also be due to the higher number of drugs taken by the patient. Newborns are more susceptible to experiencing an ADR particulary if the child is premature. This may be due to immature drug-metabolising abilities of the newborn. Sex Women tend to encounter ADR more frequently than men. The reason is not known but women tend to experienced twice the number of aplastic anemia cases due to chloramphenicol and thrice the number of agranulocytosis due to phenyl-butazone, when compared to men. Pregnancy Fetus of pregnant mothers are known to be at risk of ADR with the consequent effects vary from teratogenesis to effects on organ function depending on the time of exposure. The rapidly proliferating cells of the fetus are very susceptible to drug effects. A well-known example involved the occurrence of phocomelia induced by thalidomide. Race and genetic polymorphism Some individuals tend to develop ADR not usually expected from the drug exposure unless the patient suffers some form of deficiencies. Deficiencies may result in the alterations of how drugs are being handled in the body. Patient's underlying condition Patients with organ failure such as liver or kidney failure is at greater risk of developing ADR.The pharmacokinetic characteristics of the drug or the pharmacodynamics of drug effects may be altered under these conditions. |
How do you ascertain a suspected ADR?
ADR may present in various forms. The most common are skin rash, pruritis, fever, nausea, vomiting, dizziness, headache, and diarrhea. Other important and relatively frequent ADR include bone marrow suppression, hepatitis, nephrotoxicity, arrhythmias, and a variety of neuropsychiatric symptoms including hallucinations, somnolence, depression, and confusion. Since the array of disease associated with an ADR is so broad, any forms of clinical conditions experienced by patients should be considered as possible ADR. This should be carefully investigated through the gathering of a complete drug-taking history of previous and current medicine, both prescriptions and non-prescriptions.
Diagnosing an ADR is very a difficult and often impossible task to perform. However, several criterias may be used to establish a likelihood of an ADR. The time to onset (especially when it occur immediately following drug administration) as well as the course of the reaction upon dechallenge (i.e. reaction disappears when the drug is discontinued) or rechallenge (i.e. reaction reappears when it is reintroduced) may provide an initial clue of such a likelihood. This information together with all other information that is sufficient to rule out the role of concomitant therapies as well as non-drug related factors would be very suggestive of an ADR. For some, such reactions can be confirmed through therapeutic drug monitoring whereby the drug blood concentration is measured.
Previous reports of similar reaction associated with a drug in question may also help in ascertaing an ADR. These types of information are readily available in well-established reference sources such as Myler's Side Effects, United States Pharmacopeia for Drug Information, Facts and Comparison, Martindale, British National Formulary as well as the computerised systems including MEDLINE, TOXLINE and DRUGDEX.
How is ADR managed?
ADR, whether suspected or confirmed, should be managed accordingly, generally based on the drug implicated as well as the type and the severity of the reactions. Management maybe individualised but has to be carried out in a systematic manner.
The most logical thing to do when confronted with an ADR is to stop the offending drug immediately especially if it is not a life-saving drug and abrupt withdrawal is not dangerous. The ADR should be monitored. Most reactions will disappear promptly when the drug is discontinued. Some ADR are not serious and resolved upon continued treatment. If the reaction is severe, the patient may require emergency treatment or even need to be admitted into an intensive care. When it involves a drug that has a prolonged duration of action, measures to remove the drug from the body, such as dialysis or hemoperfusion, may even be necessary. If however the condition is not severe, what is required is just continued monitoring and consulation with a specialist to determine further action.
If the ADR is suspected to be dose-dependent, the drug may not need to be stopped. The problem may be overcome by just reducing the dose. On the other hand, if the ADR is a form of a hyper-sentivity reaction, the offending drug should be stopped immediately and permanently. Readministration of the drug is considered an absolute contraindication because reexposure can cause a reaction that can be more severe. In fact, the patient should be informed of this. Every effort to treat or attenuate the reaction should be attempted immediately. In the case of an allergic reaction, this may often be lessened by administration of antihistamines or corticosteroids.
If the patient is on a multiple drug regimen, it may be difficult to determine which drug was responsible for the reactions. Under such circumstances, all drugs likely to cause the reactions should be stopped. Once the ADR has resolved, further drug therapy must be carefully considered.
Why is reporting ADR important?
Health care provider can play a vital role in preventing an ADR. This can be done by reporting severe, unusual or previously unrecognised ADR. Reporting an ADR is actually an important means of detecting new and serious reactions. Though it cannot provide estimates of risk because the true number of cases are invariably underestimated, and the extent of drug utilisation unknown, reporting of ADR has been vital in alerting health care providers to serious ADR. It may also provide the first step towards identifying risk factors associated with it.
Effective Communications in Pharmacovigilance
Monitoring, evaluating and communicating drug safety is a public health activity with profound implications that depend on the integrity and collective responsibility of all parties - consumers, health professionals, researchers, academia, media, pharmaceutical industry, drug regulators, governments and international organisations - working together. High scientific, ethical and professional standards and a moral code should govern this activity. The inherent uncertainty of the risks and benefits of drugs needs to be acknowledged and explained. Decisions and actions that are based on this uncertainty should be informed by scientific and clinical considerations and should take into account social realities and circumstances.
Flaw in drug safety communication at all levels of society can lead to mistrust, misinformation and misguided actions resulting in harm and the creation of a climate where drug safety data may be hidden, withheld, or ignored.
Fact should be distinguished from speculation and hypothesis, and actions taken should reflect the needs of those affected and the care they require. These actions call for systems and legislation, nationally and internationally, that ensure full and open exchange of information, and effective standards of evaluation. These standards will ensure that risks and benefits can be assessed, explained and acted upon openly and in a spirit that promotes general confidence and trust.
The following statements drawn up at the International Conference on Developing Effective Communications in Pharmaco-vigilance, Erice, Sicily, 24-27 September 1997, set forth the basic requirements for this to happen, and were agreed upon by all participants from 30 countries.
- Drug safety information must serve the health of the public. Such information should be ethically and effectively communicated in terms of both content and method. Facts, hypotheses and conclusions should be distinguished, uncertainty acknowledged, and information provided in ways that meet both general and individual needs.
- Education in the appropriate use of drugs, including interpretation of safety information, is essential for the public at large, as well as for patients and health-care providers. Such education requires special commitment and resources. Drug information directed to the public in whatever form should be balanced with respect to risks and benefits.
- All the evidence needed to assess and understand risks and benefits must be openly available. Constraints on communication parties, which hinder their ability to meet this goal must be recognised and overcome.
- Every country needs a system with independent expertise to ensure that safety information on all available drugs is adequately collected, impartially evaluated, and made accessible to all. Adequate nonpartisan financing must be available to support the system. Exchange of data and evaluations among countries must be encouraged and supported.
- A strong basis for drug safety monitoring has been laid over long period, although sometimes in response to disasters. Innovation in this field now needs to ensure that emergent problems are promptly recognised and efficiently dealt with, and that information and solutions are effectively communicated.
