Clinical Trials For Rofecoxib Pharmacovigilance Biology Essay

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Drug safety is gaining popularity in recent times. Every week details about the drugs causing unexpected ADRs are being published in many tabloids and also scientific journals. All these journals and articles have an unwanted effect of invoking anxiousness in both public and prescribers about the usage of these drugs. Further worse outcome would be that the patient discontinues the usage of the drugs prescribed to him, which could be a more serious outcome than compared to the adverse drug reaction. Here pharmacovigilance comes into play. The definition given by WHO for pharmacovigilance is ''the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem'' (WHO, 2007). Pharmacovigilance ensures that physicians and also patients have sufficient knowledge for taking a wise decision in choosing a drug for treatment (Harmark et al., 2008). In this writing the pharmacovigilance of rofecoxib (Vioxx) has been dealt.


Nonsteroidal Anti-inflammatory Drugs (NSAIDs) show their pharmacological effect by the inhibition of cyclo - oxygenase (COX), an enzyme which synthesizes prostaglandin. COX has 2 isoforms, they are COX-1 and COX-2. In specific, COX-1 inhibition results in the undesired gastrointestinal problems and is the side effect of NSAIDs. On the other hand COX-2 inhibition produces the desired anti-inflammatory outcome.

In UK around 2,000 deaths occur every year in patients who are under NSAID treatment due to severe gastrointestinal problems like GI bleeding or perforation because of duodenal or gastric ulcer which constitutes to approximately 0.5 to 2 percent. Usually the patients who are over 65 years are under greater risk, especially the patients who have a history of cardiovascular events, peptic ulcer, bleeding of upper GI tract, or the patients who are under concomitant anticoagulant or corticosteroid treatment. But the fact is that chronic GI effects are caused by all NSAIDs and this risk depends on the dose and as the dose increases, the related risk also increases (DTB 2000).

Rofecoxib, an NSAID, was claimed by the manufacturer (Merck & Co.) to inhibit COX-2 selectively and was licensed for treating osteoarthritis symptomatically, for acute pain treatment, and for dysmenorrhoea. When rofecoxib was withdrawn from the market, the attention is directed towards the drug safety. The withdrawal of rofecoxib took place after it was found to cause elevated cardiovascular risk in comparison to placebo (Bresalier et al., 2005).

Effect of rofecoxib withdrawal on European regulatory:

The drug (rofecoxib) was withdrawn in European market, leading to the reassessment of total system of pharmacovigilance in various European Union member states. The results of this were reported in March 2006. This report focussed on the loopholes and strengths of pharmacovigilance system in Europe (Harmark et al., 2008)

Methods of ADR Detection:

It is the responsibility of each and every professional involved in the health care management in informing the fellow people about any adverse drug reactions or therapeutically important ADRs, which they detected. This information may be given even apart from the formal data collection programmes because not doing so may result in the further continued usage of a particular drug by other investigators too in the clinical trials or in general prescription, which may lead to the occurrence of adverse drug reactions in wider population. In addition to this national centres need to be informed with about the event and also the procedure with which it was diagnosed. These national centres are in turn responsible in sending the information to World Health Organisation which takes necessary regulatory action to try and terminate the adverse drug reactions. WHO maintains a huge database which contains around two million reports from all over the world. This worldwide information is then analysed by World Health Organisation Collaboration Centre which now uses artificial intelligence in analysing these reports. This information reviewed by WHO supports all national centres around the world which are around fifty nine (Edwards et al, 2000). Detecting adverse drug reactions in the early stages of drug usage is the challenge faced by all the organisations of health care. Various methods are being developed for the safety of the society and for efficient ADR reporting. Following are the different methods available for detection of adverse drug reactions:

1. Anecdotal reporting:

Anecdotal reporting is something like an argument done against the existing standard rules and procedures of treatment which sometimes prove to fail. Anecdotal reporting includes issues raised in journals by experts in various peer reviewed papers etc. This method of adverse drug reaction detection is comparatively cheaper and simpler than other methods available. This method relies upon individual findings of pharmacovigilance and individual accurate assessment rather than observation by a group which may not be always fruitful. This method usually may detect only quite common effects (Wood and Coulson, 1993)

2. Organised voluntary reporting:

Voluntary reporting may be done by any of the medical health care professionals who detect adverse drug reactions at the clinical level. This include reporting of adverse drug reactions by doctors, pharmacists and pharmaceutical companies. This reporting also includes computerised systems like yellow card system, which is being followed by World Health Organisation and "Food and Drug Administration's Adverse Drug Reaction File System" which is being followed by FDA. This is comparatively faster than other methods available. It is also simpler compared to other methods. This method of ADR reporting may sometimes result in under-reporting. Reporting may get biased by "bandwagon" effect (Inman, 1981).

3. Intensive event monitoring:

This is done by conducting time to time regular visits to the hospitals where clinical trials are being conducted. If any adverse drug reactions are observed in a particular site then the necessary actions are taken and reporting of these adverse reactions will be done immediately (Wood and Coulson, 1993).

4. Cohort Studies:

Cohort studies are conducted with an aim of obtaining evidence to refuse the existing relation between the cause of a disease or an adverse reaction and effect of it. Cohort study is also called panel study and is a type of study design which involves a group of people who are subjected to a particular drug. For example, a group of peoplde being treated with statins. Cohort studies are done by comparing the outcome of a drug with a general population or with individuals of another cohort. In a cohort study the individuals are observed closely for a longer period of time (Edwards et al, 2000).

5. Case-control studies:

This is a very specific type of study done with an aim of observing individuals of a particular group or a cohort. Case-control study design is very useful in providing useful data for many research questions by reducing the cost of study and the prolonged and tiresome process of collection and analysis of the data when compared to the complete cohort study (Wood and Coulson, 1993).

6. Case-cohort studies:

These studies are particularly excellent in studying rarely occurred adverse drug reactions with very higher levels of power. This method of ADR detection has got its own weaknesses as it involves very complex statistical calculations to interpret the studies successfully (Edwards et al, 2000).

7. Population statistics:

In this type of studies large number of individuals can be studied. But this detection is troublesome to coordinate the data and the standards of the data are usually of poor quality (Gelberg et al, 1991).

8. Record linkage:

This method of detection will excellently work if it has got large content or scope. But it consumes lot of time, to some extent it is expensive and it relies on only the standard data rather than including the missing data (Gelberg et al, 1991).

9. Meta-analysis:

This type of ADR detection uses the makes use of the already obtained data and analyses with the present data (Wood and Coulson, 1993).

Rofecoxib Withdrawal:

Rofecoxib must have been withdrawn many years earlier according to a meta-analysis study done for CV events with the drug. This became more and more significant from the year 2000 (S.A. Khan et al. 2006).

Clinical Trials showing ADRs of Rofecoxib:

Trial 1: Rofecoxib associated Temporary Visual Impairment.

Table 1: Trial results showing visual disturbance with Rofecoxib (David et al., 2003)

Table 2: WHO database of reports for visual impairment related to Rofecoxib and other NSAIDs showing that Rofecoxib has significantly higher incidence of visual impairment cases reported compared to other NSAIDs (David et al., 2003)

Trial 2: Rofecoxib associated Cardiovascular Events

Table 3: Results of the trial showing thrombotic adverse events caused with Rofecoxib compared to Placebo (Robert et al., 2005)

Table 4: Table showing the suggested measures for licensing a drug (Paul et al., 2004)


The failures in the drug safety had to be scrutinised thoroughly and should form a lesson for future. Since clinical trials are not sufficiently enough in detecting long-term and infrequent side effects or DIs, post-marketing surveillance had to be laid a critical importance. But the major problem here is in identifying signals of ADRs and this is because of the fact that most ADRs replicate the effects of general illness and thus making them difficult to correlate with the drug. Continuous perception of ADR signals could be of some help. The existing methods are absolutely necessary but not sufficient (S.A. Khan et al. 2006).There are quite many advances to be expected in the methods of detecting adverse drug reactions too. Computer and internet based ADR reporting is very much useful but has their own limitations in many parts of the world like third world countries where internet and computer facilities are not up to the mark. The presently used method of artificial intelligence by World Health Organisation can take up only a limited amount of data. Hence, improvements in this technique for detecting, analysing and handling of larger data from all parts of the world are required. There is a need for the improvement in the methods of pharmacovigilance and its method of communication. Government need to cooperate and encourage the voluntary organisations which show their interest in detecting the adverse drug reactions (Edwards et al, 2000). It is important to note that accumulation of the data regarding the adverse drug reactions is not the main aim of all these detection methods hence, focus had to be laid upon reducing the occurrence of adverse drug reactions.