Introductory Chapter: Pharmacovigilance

1. Introduction

Consuming a drug is equivalent to consume a risk. It is only when the benefit associated with the drugs are more than the risk, that the consumption of a drug is justified. Thus, it is benefit versus risk ratio of the drug which decides whether a drug is to be taken or not. The next question is how to measure risks and how to measure the benefits. Due to individualization of drugs to patients, it is the clinical judgment of the physician to identify what will benefit the patient. At the same time, risk associated with the drug can be ascertained by observations related to pharmacovigilance. The studies related to pharmacovigilance indicate what are the possible risks associated with the drug. Even drug can be associated with possible adverse reactions, intended or unintended. The only exception to this generality is the case of drug which is given in case of deficiency of specific components like vitamins or minerals. It is the study of possible adverse reactions of drugs which constitutes the essential content of Pharmacovigilance. This takes us to the definition of Pharmacovigilance.

Pharmacovigilance is the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. [1] Spontaneous reporting of adverse events and adverse drug reactions is the commonest method utilized for generating safety data.

Major aims of pharmacovigilance are as follows:

• Early detection of hitherto unknown adverse reactions and interactions.

• Identification of risk factors and possible mechanisms underlying adverse reactions.

• Estimation of quantitative aspects of benefit/risk analysis and dissemination of information needed to improve drug prescribing and regulation.

Safety of patient is the most important when it comes about medicines. Various types of medicines are used since ancient ages and various rules and regulation were formed in modern era. If we look back in early twentieth century, the safety of patient was discussed first time when Biologics Control Act, 1902 was passed by USA [2, 3]. After that in 1962, USA promulgated a law stating that it is the manufacturer’s responsibility to prove safety and efficacy of the drug before getting marketing authorization. In 1963, a committee on Safety of drugs was established in UK. In 1964, a system of “Yellow Cards” was established in UK to trace reporting safety of drugs by all users of drugs [4]. By 1964–1965, National Adverse Drugs Reaction reporting systems was initiated in countries like UK, Australia, New Zealand, Canada, West Germany and Sweden.

In 1962, International Center for monitoring of Adverse Drug Reaction by WHO was established in Geneva, which was later shifted to Uppsala in Sweden and this is the beginning of pharmacovigilance. From then, the WHO-supported Uppsala monitoring Centre has spearheaded many activities of pharmacovigilance all over the world (Table 1).

2. Current methods in pharmacovigilance

Pharmacovigilance is branch of pharmacoepidemiology but is restricted to the study, on an epidemiological scale, of drug events or adverse reactions.

Here ‘events’ means, recorded happenings during a period of drug monitoring in the patients notes, it may be due to the disease for which the drug is being given, some other intercurrent disease or infection, an adverse reaction to the drug being monitored or the activity of a drug being given concomitantly.

3. Causality assessment in pharmacovigilance

While reporting any adverse reaction, it is necessary to establish causal relation between the suspected drug and the observed effect. It is also possible that one of the diseases processes, interaction of the drug on disease process or even lack of effect of a drug exacerbating the disease process may be involved in the observed effect.

The causality assessment system proposed by the World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO–UMC) [20], and the Naranjo Probability Scale [21] are the generally accepted and most widely used methods for causality assessment in clinical practice as they offer a simple methodology (Tables 2 and 3).

4. Signal detection

As per World Health Organization, signal of adverse drug reaction is: “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously” [22].

A signal is therefore very tentative in nature; the first expression that something might be wrong with a medicinal product, or a hint given by new information which might support or explain a medicinal product–adverse reaction relationship already known [23].

Usually, more than a single report is required for signal detection (SD), depending on the seriousness of the event and the quality of the information. Once a signal is detected, one can then analyze and confirm it. In detecting signals from large ADR databases, however, one has to use a procedure that is sensitive (low false negativity) and specific (high true positivity) for the purpose [24, 25].

Different methods are being developed till today for the detection of signal. In that statistical method is very useful and very under estimated method. Such method is data mining approach, in which important and useful information are automatically and continuously extracted from large amounts of data, it is a form of exploratory data analysis and a key component of the knowledge discovery process. This approach seems particularly valuable and can be used on any large data set.

Data mining approach is divided into mainly two parts: frequentist and Bayesian methods.

5. Pharmacovigilance and ICH regulations

So far, pharmacovigilance-related topics entered the ICH process in two waves. The first wave resulted in adoption of the ICH Topic ICH-E2A in 1994 with an extension to this work in the form of E2B and E2C, finalized between 1996 and 1997. The second wave started in 2002 with three further ICH topics, E2D, E2C Addendum and E2E, finalized between 2003 and 2004 (Figure 1).

6. Pharmacovigilance in pediatric population

Pediatric population is defined as age between 0 and 18 years of age. Since many ages, pediatrician deals with limited available medicines specifically made for children. The reason behind limited availability of medicines is lack of clinical trials in this age group. Pediatricians are left with no choice other than prescribing it as “off-label” basis as these medicines have not been adequately tested and or formulated and authorized for use in appropriate pediatric age group. So these health care providers should be aware of risk involved in prescribing and administering such drugs to children [1].

Risk of adverse reactions increases with “off-label” use of drugs and so regulatory authorities play an important role in reminding health care providers to report adverse drug reactions and process of pediatric pharmacovigilance [31]. Specific problems associated with pediatric population are lack of clinical trials, under or over dosage, lack of pharmacokinetics and dose-finding studies; drug induced growth and developmental disorders as well as delayed ADRs [31].

Various stakeholders that play a role in pharmacovigilance are health professionals, parents, pharmaceutical industry, patient organizations, national healthcare systems, etc.

Different regulatory guidance’s available for pediatric pharmacovigilance are but not limited to:

ICHE2E

EMEA: Guideline on conduct of pharmacovigilance for medicines used by the pediatric population.

EMEA: Guideline on conduct of pharmacovigilance for vaccines.

Points to be considered for future in pediatric pharmacovigilance are [32]:

• Pediatric population should be taken into account during all phases of pharmacovigilance cycle

• Encourage ADR reporting

• Expanding definition of ADR to include off-label, misuse, error.

• Risk management plans

• Signal detecting systems

• Additional monitoring system

7. The future

The drugs can viewed, in general terms, like any other commodity. Patients will be able to choose what is best for them on the basis of information they are given. Drugs with relatively less benefit or more risk will find an appropriate market level. We believe this involves the public understanding more about benefit and risk, more suitable information coming from regulators and industry regarding benefit and risk of drugs, health professionals being able to interpret information for singular situations and the law and media playing a more constructive role in the whole process. The situation is undoubtedly more complicated than this, and the issues of communications in a crisis involving safety issues with a drug not only affect the situation but have a more general impact. These high profiles issues deserve special attention as does the impact of new communications media and sources.

Pharmacovigilance benefits everybody. The patients are protected from unsafe drugs, doctors and pharmaceutical industry keep their reputations intact and drug regulators receive pertinent data that helps them to take regulatory decisions.

It is expected that with the involvement of all related stakeholders, Pharmacovigilance program will help in reducing the cost of damages caused by drugs to minimal level. It will also try to prevent drug-related damages if appropriate care is taken by physicians on the basis of feedback from the pharmacovigilance program.