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With the advent of modern medicines, the manner of disease control and management has been changed. However, despite all their advantages, it is now discernible that, inauspicious reactions to medicines, still often preventable, reason of illness, handicap and even death. Adverse drug reactions (ADRs) take place among the top ten leading causes of death, in many countries (WHO policy perspectives on medicines, 2004). Besides this, intrinsic risks related to the drugs themselves, individual patients may manifest specific and unexpected sensitivities to the certain drugs. Above all, in multi-drug therapy, there is always an increased chance of drug interaction. So, it is indispensible to select the best and safest medicine(s) for a patient among many available options and to do that substantial acquisition is required on behalf of the prescribing practitioner (WHO policy perspectives on medicines, 2004). It is almost two decades after the thalidomide disaster, which directed our attention on the necessity of pharmacovigilance- which refers the way for monitoring and detecting ADRs (WHO, 2004), the present situation for supervising the adverse drug reactions are far away from the satisfactory level (Inman, 1981). Although it is widely admitted by epidemiologist, pharmacologist and physicians about the significant frequency of occurrence of adverse drug reaction, less attention has been paid at this field (Corrigan, 2002).
From the clinical view, (see table : 1) ADRs can be classified as type- A (augmented), when adverse effects related to the known pharmacology of the drug (e.g. bleeding with anticoagulant, sedation with anxiolytic) (Rang et al., 2007). On the other hand, type- B (bizarre) ADRs are unrelated to the main pharmacological action, usually rare but severe and do not exhibit dose-response relationship (e.g. aplastic anaemia from chloramphenicol, anaphylaxis due to penicillin) (Rang et al., 2007). Some of the ADRs can be detected when premarketing clinical trial of the drug is conducted; but the clinical trials are mainly designed for the efficacy judgement rather than the detection of ADRs. In fact these trials are primarily effective for detection of type A reaction and type B reactions are usually difficult to anticipate at these stages. As a result, when a drug product is granted for license many doubts about the possibilities of ADRs persist (Corrigan, 2002). Consequently, after marketing a drug and during its widespread use, many ADRs come forth and the rational and safe use of a new drug largely depends on this stage; phase ?V clinical trials, post-marketing surveillance studies and spontaneous reporting through the yellow card system can be beneficial at this stage for providing formal warning of potentially severe drug reactions and supervising the safety of a drug (Inman, 1981; Corrigan, 2002).
Herein some limitations and advantages of methods involved in the detection of ADRs during preclinical animal experiments, clinical trials on human and once a drug has been registered and is being used by wider population have been briefly reviewed.
Detection of ADRs during pre-clinical testing and during clinical trials on patients:
The main objective of preclinical laboratory based testing is to fulfil the requirements that need to be met before a new drug is tested for the first time in humans. Initially, pharmacological testing is conducted for the detection of harmful acute effects of drug (Rang et al., 2007). Subsequently, toxicological testing on animals is performed to extinguish genotoxicity and to fix the maximum non toxic dose of the drug (Rang et al., 2007). In addition, pharmacokinetic testing for ADME and chemical testing for assessing the stability of the chemical compounds are also carried out (Rang et al., 2007). Furthermore, teratogenicity, carcinogenicity and long term toxicity tests are also executed if the drug is required to be used for a long term in humans and in that case tests can be extended up to two years (Corrigan, 2002). Again, rats and rabbits are used for testing teratogenicity and for detecting the adverse effect of drug on reproduction (Corrigan, 2002). Although, half of the drug candidates fail to reach the clinical trial stage and for the rest to get permission from Medicine Control Agency (MCA) is not easier (Rang et al., 2007), inference of animal toxicity to human is very restricted and prediction of toxicity from these studies often fails when drugs are used in humans ( Inman, 1981).
In phase I clinical trials are performed on only a limited number of healthy volunteers (20-80) , who are young men and females are excluded due to hormonal variations which may alter drug absorption and metabolic pathways and also for the probability of teratogenic effects of drugs which may affect foetus (Corrigan, 2002). Moreover, the volunteers are required to refrain from the certain factors which may affect the metabolism of drugs like alcohol consumption, smoking, physical exercise, consumption of illegal drugs etc (Corrigan, 2002). Although, detection of common type A adverse reactions from this trial is possible, the overall ADRs can not be predicted from the strictly maintained environment of phase ? clinical trials due to low incidence of harmful drug reactions (Freeman, 1991; cited by Corrigan, 2002).
Phase II studies are conducted on 100-200 patients and principally focused on efficacy of a drug rather than the risk profile of drugs (Rang, et al., 2007).
Phase III trials are double blinded randomized trial and projected to judge both efficacy and safety of new treatment compared to the commonly available treatment (Rang et al., 2007). It is stronger than the phase ? and ?? as it involves more patients (1000- 3000) and they are selected randomly for putting into two groups. Moreover, randomisation is done by computer and neither doctors nor patients know the category (new or not) of treatment; patients receive treatment according to the provided code number by computer (http://www.cancerhelp.org.uk/trials/types-of-trials/phase-1-2-3-and-4-trials).
In fact, all the premarketing clinical trials and animal toxicity tests are more relevant to efficacy of drugs rather than the safety issue (see table: 2) and the time when drugs are marketed only a trivial evaluation of risk profile of drugs are adopted (Stricker et al., 2004).
Post marketing studies for ADRs
Phase IV trials are performed on a large number of populations and it is multi focused as well as large number of practitioners and patients are involved in this trial from different regions; in these trials long term side effects (type B) which have escaped detection during premarketing stages can be identified due to increased exposure of people to the new drug (Corrigan, 2002). Furthermore, it has also been demonstrated that the females and elderly people who were not represented during preclinical trials are included here; hence re-evaluation and setting up a new clinical indication for a drug is possible (Council for international organization of Medical Sciences, 1993).
In post marketing drug surveillance, a specific type of cohort study named as record linkage is used to detect ADRs; here information about an individual is collected by using computerised medical database and then the information can handily and cheaply applied to the follow up of patients during PMDS studies (Crombie, 1986). Further, this follow up period can be prolonged for a longer time on the basis of needs such as for the detection of long term ADRs (e.g. cancer); this system is not dependent on physicians or professionals' co-operation and it is also effective for the detection of drug induced congenital abnormalities (Crombie, 1986). The one of the limitations of this method is embedded in its source of advantage, the computerised database, which may not meet up the standard expected for medical research. Besides this, coding of disease is done according to International Classification of disease, which may not the perfect coding for the detection of possible ADRs and finally the record linkage systems are restricted to the indoor patients' events of hospital and hence only suitable for the identification of serious reactions (Crombie, 1986). In, PMS controlled experiments are also used which involves two or more treatment groups and the controls are used for another active drug or placebo (Wardell et al., 1979).In this experiment by introducing blinding of treatments and by using different variables, biasing can be avoided which can be considered its advantage but limitations of this type of experiments are patient enlisting and dropout, ethical problem with assignment of treatment and costing Again in another method used in PMS for ADRs namely case control, where individuals are selected as control who does not have suspected drug effects and frequency of drug exposure among case and controls is verified and compared (Wardell et al., 1979). However, biasing due to non randomised treatment assignment is a major drawback in this system. Furthermore, case control study is not associated with patient's compliance and data collection procedure is retrospective (Wardell et al., 1979). Therefore, case control study is not so much effective experiment regarding the incidence of side effect of a drug in comparison to cohort and control experiments. On the other hand, getting the evidence from this study is relatively cheaper and easier rather than the two and this evidence also can be used as a potent source of hypothesis for evaluation (Wardell et al., 1979). For instance, finding association between vaginal carcinoma of the female offspring and the woman who had been treated with diethylstilbestrol during their pregnancy is a successful implementation of case-control study (Sticker et al., 2004).
The most frequently and well recognised method for ADRs detection after marketing of a new drug is spontaneous event reporting (SRSs) and it provides the best method for early warning of risks associated with the newly marketed drug (Pirmohamed et al., 1998). For an example, temafloxacin was withdrawn from the market as it induced haemolytic anaemia within one week of its administration and which was confirmed from spontaneous reporting (Blum et al., 1994; cited by Brewer and Colditz 1999). In the UK 'Yellow Card' system which is designed by the regulatory authorities, where doctors are responsible for spontaneous reporting about any suspected adverse reactions by filling in details about the event on yellow card, 'Pharmacovigilence' in France and other national schemes completely based on this spontaneous reporting for the collection of ADRs data ( Fletcher, 1991). Again, spontaneous reporting about any observed specific adverse reaction by the physicians, pharmacists dentist and other healthcare professionals from different region of a country and from different health centres can generate a signal (e.g. for an uncommon adverse reaction 3-5 reports can generate a signal). When a signal is generated against a drug, data from other sources are verified and, if there is a potential risk of public health issue, regulatory authority like Committee on safety of medicine (CSM) takes step to minimize the risk and notice users (Evans et al., 2001). But in this procedure, underreporting and the question about the number of case reports required to generate a significant signal are major obstacle (Evans et al., 2001). Underreporting is most common among GPs as almost 80% of treatment is prescribed by them; they may feel unsure about notification of suspected adverse reaction and can be biased by wrongly considering that adverse reaction is already well established (Inman, 1981). This phenomenon is also evident from a study conducted by the CSM on GPs, where only 2 practitioners out of 53 reported to the CSM their patients' death from pulmonary, coronary and cerebral thrombosis while taking OCP (Inman and vessey 1968; cited by Corrigan, 2002). Another study showed that, only one adverse reaction was reported by GPs out of 1144 adverse drug reactions (Alvarez-Raquejo, 1998). Furthermore, Abraham and Shephard (1999) suggested that media coverage highlighting adverse reaction of drug has direct impact on the increase in number of SRs although this type of biased reporting is an undependable indicator for the preponderance of ADRs related to the drug. For an example, after the negative broadcasting regarding the hazard of sleeping pill, Halicon an increased number of spontaneous reports were received by regulatory authorities; thereafter this reporting was proved as contrived and greatly influenced by negative broadcasting as the drug was not more hazardous than other drugs of same category (Abraham and Shephard, 1999). Again, SRS provides large databases and for evaluating this and for generating signal data mining tools are necessary for pharmacovigilance experts Although several data mining methods like automated signal generation method, Bayesian confidence propagation neural Network (BCPNN) etc. are available, their hindrance is the production of large number of signals from which assessment of drug -event relation is not possible. So, from this point of view a suitable method should be developed which can generate satisfactory number of 'true' signals and thereafter meaningless interpretation of 'false' signals will be minimized (Roux et al., 2005).
Another efficient measure for detecting ADRs is medical literature which contains detailed case reports, not commercially biased and also assessed by reviewers for quality and it has been studied that 14 out of 18 ADRs detected by spontaneous reporting were published through the literature (Sticker et al., 2004). Despite, all released case reports are not authentic due to false positive signals, medical literature is an effective system for admonishing about new adverse reactions (Sticker et al., 2004).
Adverse drug reaction is a major public health issue and effectiveness and safety of drugs is specially a major concern especially when they are intended to use in specific population groups like children, pregnant women, and the elderly (WHO policy perspectives on medicines, 2004). It is true that society has the right to be protected against this type of adversity and there are multiple methods are available for detecting the ADRs at different stages of drug development and also during the market life of a new drug. But no single system alone is sufficient to cover all the demands for the effective collection of data which is important for establishing the relation of an adverse event with the drug; therefore numerosity of methods needs to be available for observing and quantifying the drug related adverse events and their efficient comparison then can contribute to the causality (Fletcher, 1991). Recently, it has been suggested (Sticker et al., 2004; Pirmohamed et al., 1998) that the emphasis on the expensive procedure of spontaneous reporting which is utilized by most government agencies should be diverted to the epidemiological studies as it is more useful for testing hypothesis. Furthermore, monitoring of adverse drug reaction by approaching well developed computer based system in primary and secondary health care also can be an effective measure (Pirmohamed et al., 1998). However, the significance of adverse drug reactions should be taken in account more cautiously and critically as now a days they are very common and most of the times they are life threatening and burden to the patient. So, more effort should be put into the methods available for detection of adverse drug reactions specially in post marketing stage of a drug (Stricker et al., 2004) and only then it will be possible to ameliorate the risk-benefit ratio of a treatment.
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