Pharmacovigilance

The patient had huge blisters all over his body. His skin was peeling off, and he was being treated as a case of severe burns. Despite the best efforts of the medical personnel, the patient did not survive. The patient was suffering from leprosy and was being treated with three drugs, including dapsone, which contains sulfur. A general rule of thumb I teach my students is that, any medicine which contains sulfur in its structure is likely to cause an adverse drug reaction (ADR). Doctors should be very careful while prescribing these drugs.
Modern allopathic medicines have caused a revolution in treatment and cured or controlled many diseases that previously were death sentences. Their positive effects are strongly promoted in the media by drug companies. However, these medicines also have adverse effects that usually get less attention unless a serious adverse reaction or death happens. An adverse drug reaction is a noxious or unintended effect of a drug which occurs at doses normally used for treatment. All drugs are poisons at higher doses, and so, deliberate or accidental overdose of a drug will inevitably lead to adverse effects. The ability of a drug to cause dangerous adverse effects is dependent on a parameter known as the therapeutic index by doctors. Lower the therapeutic index, more dangerous is a drug.

How are drugs tested?
Drugs are usually first tested in animals and then they undergo clinical trials in humans. Medicines are only tested in a limited number of individuals and pregnant women. Women of the reproductive age group, children, and the elderly are usually excluded. The trials are usually conducted under standardized conditions and do not mirror everyday use of drugs. In normal life, people take many drugs for different diseases and may combine allopathic medicines with complementary remedies. Hence, most drugs continue to be on the watch list for a period of time after they are marketed. This is sometimes referred to as a phase IV clinical trial. This is very important to ensure safety of a drug.

The thalidomide tragedy
In the late 1950s, the drug thalidomide was widely promoted for morning sickness. The drug was tested in pregnant animal females and no effects on the fetus were noted. As already mentioned, pregnant women are usually excluded from clinical trials. The drug was widely used among pregnant women in Europe and Australia, and led to limb deformities in the newborns (phocomelia, or seal limb). The bureaucratic processes at the United States Food and Drug Administration led to delay in approval of the drug in the country. This tragedy led to a major restructuring of the process of reporting and monitoring ADRs of medicines and is widely regarded as a key step toward the development of an international pharmacovigilance program.

How to reduce ADRs?
ADRs can never be totally prevented. Each time we take a drug, we take a risk. This underscores the importance of using medicines rationally. Some group of medicines like anticancer drugs carries a greater risk of ADRs. Many people are under the false impression that traditional and natural medicines are completely safe. This is not correct. The correct technical term for substances used in treatment is ‘medicine’. This is because of the negative connotation of drugs of abuse. In this article I will be using the two terms interchangeably. Plant products, metals, and other ingredients used can have adverse effects, and these medicines can interact with allopathic medicines, reducing or even increasing their efficacy and increasing the risk of adverse effects.
Pharmacovigilance is monitoring the adverse effects of drugs and vaccines. There is a system in place where clinics, hospitals, and individual practitioners report ADRs to a regional center and the center then reports it to the national center. In Nepal, the national center is located at the Department of Drug Administration in Kathmandu. Reporting, collecting, and analyzing ADR reports help practitioner use medicines more safely, as they have access to current data from the population.

Types of ADRs
There are multiple types, but to simplify the picture, we will only examine the two major types. One type is dose dependent. We all know that pain killers like ibuprofen and diclofenac can cause stomach irritation. The greater the dose of the drug we are taking, the higher will be the risk. This ADR is predictable. The other type is not dose dependent and may often be due to an immune response by the body to the foreign chemical that is the drug. The classic example of this type is penicillin allergy. Even a very small dose can cause a severe allergy. This is often difficult to predict the first time it happens.

International program on pharmacovigilance
As we saw earlier, the thalidomide tragedy spurred the development of international cooperation in drug safety. In 1971, an international database for ADRs was established at Geneva, and since 1978, the database has been maintained by the Uppsala Monitoring Center (UMC) in Uppsala, Sweden, which is the international center for ADR monitoring. Over 150 countries are members of the program. Nepal joined the program in the early 2000s. Regional pharmacovigilance centers have been established in different teaching hospitals in different parts of the country. The national centre is at the Department of Drug Administration in Kathmandu, Nepal. The major challenge for Nepal is under-reporting of ADRs due to various reasons. The United States accounts for the majority of ADR reports. In addition to institutions, pharmaceutical companies also report ADRs.
Process of reporting of ADRs
Usually, medical personnel notice an ADR in their patient or the patient can report the ADR to the medical person. The medical personnel manage the ADR in the patient and reports the same to the local, regional, or in some cases, the national center. The personnel at the local center do three important analyses on the ADR. They check the causality (a particular drug has caused a particular ADR), preventability, and severity of the ADR (if a patient is hospitalized, then the ADR is more severe). The ADR is eventually reported to the Uppsala Monitoring Center, which is the international center for ADR monitoring. The center analyses the ADR using a variety of techniques. One of the objectives is to generate a signal that provides an idea about how likely a particular drug is to cause an ADR. This analysis guides the safety classification of a drug, determines the precautions and contraindications, and may sometimes even lead to withdrawal of a drug from the market.

Why reporting ADRs is important?
As we have seen, clinical trials cover only a very limited population and women in reproductive ages and children, and many conditions of daily use of a medication are not included. In normal life, medicines are taken with a number of other allopathic and even herbal and ayurvedic medicines and with a variety of foods. Continuing to monitor the medicine under conditions of everyday use through the process of pharmacovigilance can help us obtain current data. Also, each population and country is unique. Nepal is a highly diverse country, and one of the best ways to obtain information about medicines in a Nepalese population is through ADR reporting. Based on the ADR reports, the regional, national, or sometimes, even the international center can provide instructions modifying or restricting the use of a medicine. Vigiaccess (www.vigiaccess.org) is a freely searchable international database about ADRs. All the data submitted to the Uppsala Center is analyzed, and the public can view data on suspected ADRs from various medicinal products.

Consumer reporting
of ADRs
Consumers can play an important role in reporting ADRs. With increasing levels of education and economic development, consumers are interested in taking an increasingly active role in safeguarding their health. Many countries have experimented with allowing consumers to report ADRs directly to the centers. The United States, Canada, and New Zealand were pioneers in allowing consumers to directly report ADRs. In 2012, the European Union mandated all member states to introduce consumer ADR reporting. In Europe, the Netherlands, UK, Denmark, and Sweden were the pioneers. One of my former colleagues has done some early work on consumer pharmacovigilance in Nepal.

Use of mobile apps for ADR reporting
In today’s world there is an app for nearly everything. Apps are being developed and tested for reporting ADRs. Apps should be customized according to the target population. The requirements for reporting by medical personnel and by lay people will be different. Apps have the potential to speed up and simplify ADR reporting. They can also help in the transmission of data from the regulatory agencies to various end users and help in improving safe use of medicines.

Safe use of medicines
is a journey
Safe use of medicines is a journey, and not a destination. Even with proper use of drugs and the best reporting systems, ADRs can only be reduced and not totally prevented. Read about the medicines which you have been taking– both those prescribed by a doctor and those which you are taking on your own. Kindly follow the instructions for taking these medicines. Tell your doctor or prescriber about all medicines you are taking, including Western medicines and herbal and dietary supplements. Also inform your doctor about other medicines from the ayurvedic and homeopathic system that you may be taking. As mentioned earlier, the common impression that these medicines are totally safe is not true. They can affect the working of allopathic medicines, and in some cases can speed up or slow down their breakdown. If you develop any problems with your medicines, do inform your doctor. Reading through the list of adverse effects can sometimes be frightening. Take a rational balanced view of the matter. Many of the more dangerous adverse effects are very rare. Be aware but do not be frightened and paranoid. Safe use of medicines is a long and important journey on which doctors and patients should travel together.