Pharmacovigilance can be defined as the science and activities relating to the detection, assessment, understanding and the prevention of adverse effects or any drug related adverse events (WHO, 2002) It is further defined as "the process of evaluating and improving the safety of marketed medicines" (Waller et al.,1996,).Pharmacovigilance assesses the risk benefit ratio of a drug. Taking medicine entails a certain amount of risk. No drugs are risk free and all drugs have potential safety concerns. Zero risk does not exist (Breckenridge, 2003). When deciding whether or not to undertake an activity, the benefit is weighed against its risk. Similarly, with the licensing of medicinal product for marketing, regulatory authorities assess drugs on the basis of the balance of their benefits and risk and the demonstrated benefit must outweigh the risks (Claude, 2001; Murphy, 2006). Pharmacovigilance regulation started in the aftermath of the thalidomide tragedy in the 1960s (Burley, 1988). More drugs have been withdrawn from the market after the thalidomide tragedy due to safety concerns. Despite the establishment of pharmacovigilance systems on a global basis, adverse drug reactions are still a major worldwide cause of morbidity and mortality. Knowledge of the safety profile of a medicine is a continuously evolving process and new information on its safety mirrors this evolution. Most elements that shape the safety profile of a drug start to gather during development (Tsintis & Mache, 2004).
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Pharmacovigilance in a drug life cycle starts from pre clinical safety data (this includes in vitro-test tubes testing) animal testing( in vivo,) toxicity testing in animals which include repeat dose toxicity, reproductive/ developmental toxicity, neprotoxicity, hepatotoxicity, genotoxicity, carcinogenicity, general pharmacology experiments-which included cardiovascular including QT interval prolongation and drug interactions) ICH E2E, 2004.
Clinical trials in humans (Phase 1 to 3) and post marketing surveillance studies phase 4 and observational studies also involve pharmacovigilance in a drugs life cycle Human safety issues are always ongoing through out the life cycle of a drug and information relevant to understanding these issues come from a multitude of sources. The clinical trial phase 1 to 3 is govern by EU Clinical trial directive (2001/20/EC) and phase 4 studies including post authorizations studies , observational studies are govern by Volume 9A.
Phase 1 clinical trials involve the testing of the new drug in a small number of healthy volunteers. These trials assess the safety (pharmacovigilance), efficacy, pharmacokinetic and pharmacodynamic properties of the new drug compound. These trials involve dose escalation where the appropriate therapeutic dose is determined.
The dose of the drug administered is a primary determinant of drug safety, and the major aim of clinical drug development is to establish a safe and efficacious range (Haas, 2004).
Phase 2 clinical trials involve the use of the new compound in actual patients with the disease this drug is meant to treat. This phase also continue to assess the dose and efficacy of the new compound.
Phase 3 clinical trials involve multicenter and randomized studies and it could include up to 3000 patients. The safety and efficacy of the drug is also assessed in this phase. It also involves comparing the safety and efficacy of this new drug to an established drug currently on the market (comparator) or to a placebo with no active ingredients. This is the last phase before an application is submitted for the licence to market this new drug.
Any adverse drug reactions occurring during these clinical trials are expeditiously reported to the concerned regulatory authorities and the concerned ethic committees.
During the clinical trial phases (1 to 3) an annual safety report is produced to provide information to the regulatory authorities and ethic committees about the safety profile of the investigational medicinal product.
After market authorisation is received for an investigational medicinal product, the new drug in the UK for example is assigned a black triangle status. These drugs are closely monitored for up to about two years or more and all Healthcare professionals and the marketing authorisation holder are to report all serious adverse drug reactions to the Medicines and Healthcare Products Regulatory Agency (MHRA) within 15 calendar day. In accordance with volume 9A, the marketing authorisation holder for the newly licensed drug is required to produce Periodic Safety Update Reports (PSURs) and submit to countries where the product is licensed in the European Union. This periodic report provides the safety profile of the new marketed drug in a large population not necessary covered during clinical trials and rare adverse reactions come to light. As part of the marketing authorisation approval condition, the marketing authorisation holder may be committed to perform post authorisation safety studies usually phase 4 studies and other observational studies as detailed in the EU risk management plan (ICH E2E, 2004) submitted as part of the dossier for obtaining a licensed for the drug.
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In accordance to volume 9A, "a risk management system is a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent and minimise risk relating to a medicinal products including the assessment of the effectiveness of those interventions and the aim of risk management system is to ensure that the benefit of a particular medicine exceed the risk by the greatest achievable margin for the individual patient and the target population as a whole. This can be done either by increasing the benefits or reducing the risk but by its definition, risk management focuses on reducing the risk".
The pharmacovigilance management of a medicinal product comprises of pharmacovigilance specification and pharmacovigilance plan. The specification provides a summary of important knowns and unknowns about a medicinal product. It will include the safety risk identified at the licensing stage, potential risk and any important missing information. The elements will form part of the pharmacovigilance plans (Tsintis & Mache, 2004). Dialogue and common understanding between regulators and pharmaceutical industries will play a key factor for developing pharmacovigilance plans during the life cycle of medicines. Appropriate interaction with health professionals and patients should also be planned for the future as regulatory seem to be more transparent.
In conclusion, pharmacovigilance activities begins at the first phase of a drug life cycle (pre clinical), continues through the second phase (Clinical trials) and in the final phase (post marketing). Pharmacovigilance activities are ongoing for a pharmaceutical drug despite the post marketing phase. Results of this pharmacoviglance actives post marketing phase has led to the withdrawal of some medicines from the market or restricted use of some medicines in certain age group or patient disease to minimise risk and increase the benefit of the drug.
The second part of this article will look at the factors that led to the withdrawal of aspirin in children and resulted in a warning that aspirin should no be used in children under the age of 12 by the Committee on Safety of Medicines (CSM) in the UK.
Factors leading to the withdrawal of children's preparations of Aspirin.
Aspirin is an antipyretic (use to control fever) and also anti inflammatory agent. Aspirin major preventive role is as an anti-platelet agent in cardiovascular disease (Langford, 2002 and ATC, 1994). Aspirin is used in the treatment of children that have a viral illness such as flu like symptoms, chickenpox or other febrile illness (Mann, 1986).
An initial link was associated with the use of aspirin and Reye's syndrome based on four case control studies from the USA between 1978 and 1984. These studies led the surgeon general in the US to advise against the use of aspirin in 1982 and the advice was reversed later that year amid growing criticism over the conduct of the four case control studies which will be discussed later in this article (Hall, 1987).
Reye's syndrome was first described in 1963 by Rye as a clinopathological entity (Rye et al., 1963). Reye's syndrome (RS) is defined as a rare but severe acute encephalopathy complicated by fatty degeneration of the liver and other viscera predominantly affecting children (Hall, 1986 and Hall, 1987). In children, RS is characterised by sudden onset of profuse persistent effortless vomiting, followed shortly with alteration in conscious level. Elevated liver enzymes are also noted. The precise aetiology of Reye's syndrome is unknown but it is believed to be multifactorial, resulting from an abnormal reaction to a viral infection in a genetically susceptible host which is modified by an exogenous toxin (Sullivan-Bolyai &Corey, 1981).
Epidemiology case control studies linking Reye syndrome to Aspirin usages
The four case control studies including the pilot study and main study are described below:
Case Control 1(Starko et al., 1980)
This case control was conducted in Arizona in the US in December 1978 during the outbreak of influenza A. The study was made of seven patients with Reye's syndrome and 16 unwell classmates as controls. It was found that all the seven patient s had taken salicylates and only eight of the 16 controls ingested salicylates (P<0.05). The patients ingested larger doses of salicylates than the control group (P<0.1). The patients appeared to have larger doses of salicylates intake when compared with the eight control subjects who took salicylate (P=0.08). Febrile patients administered salicylates more frequently when compared to control subjects with fever (P<0.01). The ingestion of salicylate was correlated with the severity of Reye's syndrome (P<0.05). A dose response relationship was postulated by Starko et al. (1980).
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A small number of children where studied in this report in addition, there was a potential of ascertainment bias which may result due to interviewing parents with a severely unwell child. In addition, the dose response relationship reported above was not observed in the later case control studies yet to be described below. The studies relating severity to serum salicylate levels have been criticised because of nonspecificity of the methodology (Clark et al., 1985 & Hall, 1986).
Case Control 2 (Waldma et al., 1982)
This case control study was conducted in Michigan during the winter of 1979 to 1980. This report describes two community based interview studies with parents of children with RS and matched controls. The first part is discussed here was done after the outbreak of influenza B. 56 cases of Reye's syndrome in school age children were reported to the Center of Disease Control in the US. The parents of 25 of these children were interviewed in the spring of 1980 as were control subjects matched to age, race, school grade and nature of any antecedent viral illness. This study showed that more children with Reyes syndrome where more likely to receive medication containing aspirin during their viral illness (24 out of 25 cases) than controls which were 34 out of 46 (Mann, 1986).
Case Control 3 (Waldman et al., 1982) part 2
This second study was done in Michigan during the winter of 1980 to 1981 to examine the observed difference more carefully for the first part discussed above. It was found that more children who had Reye's syndrome had ingested aspirin containing products during their viral illness (12 out of 12 cases) than control subjects (13 out of 29). The data presented from these two studies show that children with Reye's syndrome were more likely to have received medications containing aspirin than children with similar illness in whom Reye syndrome did not occur (Waldman et al., 1982).
Criticism of case control 2 and 3 (Hall, 1986)
There was a possibility of selection bias. This also applies to case control 1. Did all the cases have Reye syndrome? Was it certain for example that patient with aspirin toxicity were not included? In addition were controls equally at risk of developing of developing Reye syndrome in respect of all other parameters except aspirin usage. There was a potential of recall bias. Memory was worse for controls than cases because the event was less significant and interviews took place after a long interval than for cases.
Thirdly there was a data collection bias in these 2 studies. The interviewers were aware of the research hypothesis and of the designation of the subjects (case or control). Product identification was more accurate for controls than for cases.
Case control 4 (Halpin et al., 1982)
This study was undertaken in Ohio, 97 cases of Reye's syndrome occurring between December 1978 and March 1980 were compared with 156 control subjects matched for age, race, sex, geographical location and type of illness. The use of aspirin was found to be significantly different between the cases and controls: 94 (97%) out of 97 cases compared to 110 (71%) out of 156 controls had taken aspirin. This study showed that aspirin at normal doses was associated with Reye's syndrome. The criticism stated above also applies to this study.
Case control 5 -Pilot study (Hurwitz et al., 1985)
In response to the concerns arsing from the four epidemiologic case control studies previously discussed in the preceding paragraphs above this fifth case control study was undertaken in the US to address the methodological issues and the limitations of the four studies including the possible differences in the ability of case and control parents to recall and verify medications administered and differences in the severity of the matched antecedent illness for which case and controls received medications and possible misclassification of non cases as case of a Reye syndrome. This study was conducted between February and May 1984. Thirty patients with confirmed diagnosis of Reye's syndrome by an expert and 45 controls were matched for age, race, antecedent illness (respiratory infection, chickenpox or diarrhoea) and selected from the same hospital, emergency room or school, or identified by random digit dialling. There was a significant amount of cases (93% ) 28 cases out of 30 than members of the four control groups or all control groups combined (46%, 66 out of 145) that received salicylates during the matched antecedent illness (odds ratio of all 30 cases vs. all controls was 16.1;lower 95% confidence limit was 4.6. This pilot study suggested an association between Reye's syndrome and salicylates use during an antecedent illness (Hurwitz et al., 1985).
Criticism of the pilot study (Hall, 1986)
Hall (1986) stated that the methodology of this pilot study still retained the potential for serious biases. The fact that there is a widespread knowledge of association means that there could have been a preferential diagnosis and or reporting of patients with diagnostic criteria and a history of aspirin ingestion. Secondly, parents may consciously (with litigation in mind) or unconsciously have reported aspirin use once they knew the diagnosis.
Case control 6- Main study (Hurwitz et al., 1987)
Following the completion of the pilot study, a main study concerning the possible association between Reye's syndrome and salicylate was undertaken. Twenty seven patients with sage 2 or deeper Reye's syndrome whose diagnoses were confirmed by an expert panel and who had appropriate antecedent illness (chicken pox, respiratory illness) prior to the onset of Reye's syndrome were compared with 140 controls matched for age race and timing of antecedent illness. This study just like the pilot study described above also showed a strong association with ingestion of salicylates during the antecedent illness prior to the onset of RS was observed (Hurwitz et al., 1987).
Committee on Safety of Medicine decision (CSM)
The British Reye's syndrome Surveillance Scheme study was set up in the UK. There were 229 reported cases in the UK. One hundred and six parents were interviewed to obtain a detailed review of possible aetiological factors. A clear trend was established showing that a greater proportion of the children with the most cut diagnosis had taken aspirin.
On the basis of the preceding evidence from the 6 case control studies described above and the new data from the British Reye's syndrome Surveillance scheme, the CSM issued a warning on the 26 March 1986 that aspirin use in feverish illness may be a contributory factor to RS in some children and there was a need to reduce the use aspirin in children. In June 1986, the committee recommended that aspirin should not be given to children aged under 12 years except on medical advice (risk minimisation) and paediatric aspirin where withdrawn from general sale (CSM, 1986).
Although the evidence presented is conflicting but the accumulated evidence to date together with the seriousness of Reye syndrome has made me to agree with the decision of the CSM at the time. The risk has been minimised with the withdrawal of paediatric aspirin.
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