Signals Derived From Spontaneous Reporting

In many cases the initial signal will consist of a case series of similar adverse reactions occurring with a particular medicine. The principal factors that need to be taken into account in the assessment of such signals are given in Table 9.3. Broadly this consists of the details of the cases themselves and other evidence which may provide insights into the issue.

The cases producing the signal need to be reviewed individually. Evidence for causality in individual cases can be assessed by a number of methods (Meyboom et al., 1997; Edwards and Aronson, 2000). At this stage further information

Table 9.3. Factors influencing the initial assessment of a possible hazard arising from a case series.

Evidence to be considered Underlying issue

1. The cases producing the signal Individual case assess- Causality ment: temporality, effect of dechallenge/rechallenge, alternative causes (see Table 9.2)

Quality of the information Documentation regarding cases

Number of cases in relation Frequency/reporting to usage of the medicine rate

Severity of the reactions 1 Implications for patients Seriousness of the hazard J and public health

2. Other evidence

Pharmacological or Mechanism toxicological effects of the drug

Known effects of other drugs in the class

Pre-clinical studies

Clinical trials

Possible class effect

¡Existence of other evidence which may support or refute the signal on the cases may need to be obtained but may take some time to gather. This does not, however, preclude an initial view as to whether the problem warrants further evaluation. A large number of poorly documented cases of an adverse reaction which has important consequences for users (e.g. because they are serious and/or potentially preventable) will at least warrant consideration of other evidence whilst further information is being obtained. However, the greater the number of cases in relation to usage and the better documented they are, the greater will be the need to investigate the problem fully. It is important to establish a case definition and to clearly identify those cases which may provide reasonable evidence of a drug-related hazard (the cardinal cases). A view of the case series as a whole should be formed in addition to assessments of the individual cases. Depending on the quality of data, the same number of spontaneous reports and the same level of usage may provide good or poor evidence of a hazard. The key difference is often whether or not there are frequent alternative causes (these are often called ''confounding factors'').

Consideration of Alternative Causes

Table 9.4 lists the explanations other than a causal relation between suspect drug and event which need to be considered. The most common alternative causes are concomitant medication and coexisting disease. In the first case, the adverse event is a reaction to a drug and the issue is which drug is implicated, or sometimes whether there might be an interaction between two drugs. A common

Table 9.4. Possible explanations for a reported ADR other than a causal relationship between suspect drug and the adverse event.

1. Related to medication

(a) Single other drug—recognised cause

(b) Single other drug—unrecognised cause

(c) Combination of drugs (may include suspect drug)

(a) Coexisting disease unrelated to indication for suspect drug

(b) Complication of indication for suspect drug situation is that there is an alternative explanation because the patient was concomitantly exposed to a drug which is recognised to cause the adverse reaction in question. An example might be a patient with schizophrenia taking chlorpromazine who is also given a new antipsychotic drug and develops hepatitis. The reporter may suspect either drug or both, but is much more likely to report it if the new drug is suspected. Clearly, such a case of suspected hepatitis due to the new drug may not have been caused by it but there are several reasons why it might have been reported. In some cases the reporter will have been unaware of the recognised adverse reaction or the reporter may have had good reasons (perhaps relating to the temporal relationships of drug administration and the reaction, or response to dechallenge) for suspecting that the new drug is implicated.

The situation where the patient has been taking two or more medicines, none of which is recognised to produce the suspected adverse reaction, is also common. Only one drug may be suspect— often because the event occurred shortly after its initial administration or because the drug is new— but sometimes all the drugs are listed as suspect. In these circumstances it may be possible to form a view of the most likely cause or combination of causes, based on pharmacology, temporality and dechallenge. However, often no clear judgement can be made and formal studies are needed. This is particularly likely when patients start taking multiple drugs simultaneously as in highly-active anti-retroviral therapy.

Possible interactions are often particularly difficult to interpret when the signal arises from spontaneous reporting. The number of cases is usually very small and a watching brief would usually be an appropriate initial response in the absence of one or more of the following circumstances: (1) there are several plausible cases; (2) the reported cases provide objective evidence of interaction (e.g. repeated laboratory measurements during periods of single and dual drug exposure); (3) there is a plausible mechanism based on the known pharmacokinetics and pharmaco-dynamics of the drugs which has not yet been investigated in formal interaction studies (in which case such studies should be initiated); or (4) the drug has a narrow therapeutic index and the suspected adverse reactions reported are serious.

Often the major alternative explanation for one or more suspected ADR reports is that the event was not an ADR but was a naturally occurring disease which may or may not be related to the indication for the suspected drug. Since most ADRs are similar to diseases that occur naturally (a notable exception is fibrosing colonopathy with high-strength pancreatic enzymes (Smyth et al., 1995)), this explanation almost always requires consideration. A recent example for which the possible roles of drugs and underlying diseases is still not resolved is the occurrence of lipodystrophy and various metabolic abnormalities in patients treated for HIV infection.

Two important factors to take into account are the rarity of the disease in the population and whether or not the disease is related to any intercurrent illness, including the indication for the suspect drug. A series of cases of a rare disease occurring in relation to exposure to a particular drug is much stronger evidence of an association than a similar series of cases of a common disease. This does not mean that drugs are less likely to cause common diseases but that such associations are harder to detect. When the suspected adverse drug reaction is a complication of the underlying disease for which that drug was given, spontaneous reporting is likely to be unhelpful. Whilst it is possible that a drug may increase the risk of the complication developing (e.g. re-perfusion arrhythmias with streptokinase), data from a formal study measuring risk are almost invariably required in order make a satisfactory judgement about the issue.

In some of the circumstances described above, information derived from a series of cases is, by its nature, unsuited for making the necessary judgements. In this situation the possible implications for public health and the other evidence listed in section 2 of Table 9.3 are the key factors in determining whether and how to progress the issue. If the cases are scanty and most are associated with reasonable alternative explanations, a watching brief is likely to be the most appropriate course. At the other extreme, a well-documented series of cases of a particular suspected ADR without obvious alternative explanation and/or with evidence of a possible mechanism should rapidly lead to consideration of both what further investigation may be warranted, and what action is needed to minimise the risks. Many issues come between these extremes and require careful consideration of evidence from various sources and of the possible ways in which the issue might be investigated further.

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