ADR is detected by the following two methods:
- 1 Pharmacovigilance
- 2 Epidemiological methods
Pharmacovigilance (Spontaneous Case Reports and Record Linkage Studies)
Pharmacovigilance is a branch of clinical pharmacy in which drug-induced unknown adverse effects and their risk factors are detected and studied to prevent iatrogenic disease and promote the safe and rational use of drugs. The WHO defined pharmacovigilance as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problem”. The newly marketed drugs should be studied so that their undesirable and unexpected effects can be determined. Clinical trials can produce limited data regarding the rare and unexpected adverse effects. The drug-related knowledge increases with time, and this is essential for post-marketing investigation, i.e., safety evaluation of a drug that has been approved for marketing to provide alert signals about the possible adverse effects the drug may cause.
Monitoring of Adverse Drug Reactions
The process of detecting an adverse drug effect consists of:
- Hypothesis generation
- Hypothesis strengthening and preliminary assessment of the available data
- Signal testing, evaluation, and explanation.
A signal is defined as a set of pharmacological, pathological, or epidemiological data and arguments establishing a hypothesis that is significant for the rational and safe use of a drug in humans. These signals are derived by making observations in a patient or i n populations or from experimental studies.
Spontaneous Case Reports
The spontaneous case reports include the results obtained after post-marketing surveillance of drugs. Such reporting has been started since the 1960s in developed countries, where a spontaneous reporting system was developed for collecting the data of ADRs voluntarily. Generally, reports obtained from ADRs are available in national drug formularies or drug bulletins. Spontaneous reporting systems provide information about serious and unpredicted drug reactions. They are relatively inexpensive „early warning systems‟ that inform about any potential problems observed during the post-marketing phase of a drug. Once the clinical trial is completed, the drug is marketed and prescribed to a population that usually differs to a great extent from the population on which it was tested during the clinical trials (e.g., elderly people, people with co -co-co-morbidity patterns that differ from the trial populations, pregnant women or children). Spontaneous reporting systems do not provide any information about the population consuming a certain drug and the duration of therapy. These systems do not calculate the frequency of ADRs and also do not compare ADRs between drugs; therefore, pharmacoepidemiological studies are performed. There are a large number of under-reported cases with a spontaneous reporting system. Almost 90% of prescribers never report a suspected ADR and also reporting rates are rarely stable over time. It has been observed that pharmacists report more frequently, but are less aware of an ADR because patients contact to physician or doctor and not their pharmacist about the adverse effects.
The reasons behind the under-reporting are named the seven deadly sins by Inman in 1986
- Satisfaction with the wrong belief that only safe drugs are allowed to be marketed and prescribed.
- Fear of any legal action.
- A feeling of guilt because the patient’s health has been harmed by the drugs prescribed by a doctor.
- Ambition to collect and publish a personal series of cases.
- Lack of desire for reporting.
- Hesitancy in reporting measly doubts which might lead to mockery.
- A person is not bothered to report the ADR.
Under-reporting of ADRs may lead to various problems that are characteristic of spontaneous reporting systems:
- The frequency of ADRs remains unnoticed most of the time.
- Causing delayed detection of ADRs.
- A significant under-reporting may not be random but a selective process. For example, reporting rates of a newly launched drug are generally higher during the first year.
Many countries have tried to improve the reporting rates of ADRs and for this purpose, they have developed methods of feedback to reporters. This feedback includes a preliminary evaluation of a reported adverse case, therapy advice on how to deal with the adverse action, recording the report by a telephone call, a personal visit, occasional publication of a case series in scientific medical journals, or regular publication of recently reported ADRs. It is a common method of raising doubts about drug-induced diseases. If a physician doubts that an undesirable condition occurring in a patient is because of a particular prescribed drug, he/she reports it either in a letter to the medical journals or to the drug manufacturer. This alerts the other physicians and they avoid prescribing that drug. Spontaneous reporting agencies are set -up to collect and gather such case reports. Although the resulting information collected gives no idea of the frequency with which a given event is caused by a drug, it indicates that several prescribers feel that the event is possibly drug-related.
Advantages of Spontaneous Reporting
- This reporting process is relatively cheap.
- A medicine can be monitored throughout its life.
- Monitoring of over-the-counter medications and herbal therapies is also possible.
These methods are included under passive surveillance systems. The efficiency and accuracy of these systems depend on the ability of health professionals to identify potential ADRs and differentiate them based on symptoms related to underlying disease. Here it is essential to know that only a suspicion of a causal link between a drug and an adverse event is sufficient, and confirmation of the association is not required. The main drawback of spontaneous reporting systems is their inability to quantify the risk. These systems only provide information on the number of cases of ADRs reported and not the incidence of reactions because the population exposed to the drug cannot be accurately determined. Along with this, only a few reactions of ADR are reported. However, spontaneous reports are important evidence that leads to drug withdrawals and are crucial for generating hypotheses.
Record Linkage Studies
Details regarding the cause of death (as recorded on the death certificate) or of hospitalization (as recorded on the discharge letter) are collected and analyzed routinely. This provides an early warning of an epidemic of drug-related disease. Record linkage studies can be used to facilitate the research for drug-induced disease. Medical record linkage uses computer and related software to study the life and health events (birth, marriage, death, hospital admission) of the population along with prescription event monitoring and history of drug use. They are developed till resources are available.
The various epidemiological methods are:
1) Case-Control Studies:
In these studies, a group of patients having a disease assumed to be caused by a drug (the „cases‟) is compared with another group of patients not having the disease (the „controls‟). Drug histories of the cases and controls are compared. If the disease is caused by the suspected drug, the drugs have been extensively used in the cases that are in the control. Such case-control studies are performed at relatively low cost; however, they should be conducted properly and the obtained data should be appropriate.
During the case-control studies, the following precautions should be taken:
- Selection of cases should be performed carefully.
- A clear, precise, and accurate description of the disease should be given. The disease under study should have a reasonable risk of being drug-induced.
- The controls defined should be according to the population of cases but not according to the disease of interest. Controls are usually the hospitalized patients.
- The results should be determined accurately and precisely.
2) Cohort Studies:
The cohort is a group of recipients of drugs of interest and studies involve observing them for different periods to check what happens to them. These studies are used for short-term clinical trials of new drugs. Cohort studies are beneficial in detecting predictable adverse effects arising due to excessive pharmacological effects during or after short-term treatment.