Project Report on Pharmacovigilance
Subject: Pharmacy | Topics:


1.1.  Objective of the study

Pharmacovigilance was studied to measure the safety of medicine. To measure the adverse effect and problems caused by medicine. To measure pharmacovigilance of drug I analyzed the data of national drug regulatory authority, international health organization, world health organization and clinical practice of pharmacovigilance and other international research work. And more objective are:

  • To describe the scientific characteristics of pharmacovigilance.
  • To describe the  practice of pharmacovigilance in the pharmaceutical industry.
  • To describe the Pharmacovigilance in pediatrics
  • To describe the drug regulation of pharmacovigilance
  • To describe the Importance of Pharmacovigilance
  • To monitor the safety of medicinal products

1.2. Methodology of the study

I have analyzed Pharmacovigilance based on information obtained from internet, studied concerned articles and journal and creating database from secondary data processing. This chapter of the thesis describes the population & the subjects of the study, data collection, the measuring instrument, tool, & the analysis method. The methodology of the present study includes searching of the followings-

  • National and international regulatory requirements of pharmacovigilance.
  • Scientific characteristics of pharmacovigilance.
  • The future of pharmacovigilance.
  • Pharmacovigilance problem with drug interaction.
  • Epidemiological studies of pharmacovigilance.
  • Communication with healthcare professionals and patients.

1.2.1. Data source and Data analysis

The study has been done on the basis of secondary data collected from internet search and literature survey, analyzed the data of national drug regulatory authority, world health organization and the  survey of clinical practice of pharmacovigilance. Prior to analysis, data collected from various sources were processed further for making them suitable to the needs of the present study. Collected reports, books, interviews were analyzed in the light of the drug poisoning.

1.3. Rationale of the study

Pharmacovigilance is one of the most important and challenging area for the pharmacist. When a pharmaceutical drug is introduced in the market there are still a lot of things that are unknown about the safety of the new drugs. These medicines are used by various patients for different diseases These people might be using several other drugs and must be following different traditions and diets which may adversely affect the impact of medicine in them. Also the different brands of same medicine might differ in the manner of their production and ingredients. Additionally, adverse drug reactions might also occur when drugs are taken along with traditional and herbal medicines that has also to be monitored through pharmacovigilance. In some cases, adverse drug reaction of certain medicines might occur only in one country’s or region’s citizens. To prevent all undue physical, mental and financial suffering by patients, pharmacovigilance proves to be an important monitoring system for the safety of medicines in a country with the support of doctors, pharmacists, nurses and other health professionals of the country.

1.4. Limitations of the study

The report an investigation about Pharmacovigilance is mainly based on the secondary data collected from various sources. We believe that estimates data of this report do not represent the total of the global Pharmacovigilance available in Bangladesh. And also the poorly understood impacts of the mentioned special information may be due to lack of academic education. This report created only by information collected from internet, journal, books like clinics in geriatric medicine and pharmacovigilance, pharmacovigilance in clinical practice, practice in pharmaceuticals industries etc. where the information of a few subject like children’s and elder patients according to these source.


2.1. Definition

Pharmacovigilance is the science associated with detection, assessment, understanding and prevention of adverse effects of drugs. According to the Pharmacovigilence definition given by WHO, it is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Recently, its concerns have been widened to include herbals, traditional and complementary medicines, blood products, biologicals, medical devices and vaccines”.
Pharmacovigilance is the process of:

  • Monitoring the use of medicines in everyday practice to identify previously unrecognized adverse effects or changes in the patterns of adverse effects
  • assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use
  • providing information to healthcare professionals and patients to optimise safe and effective use of medicines
  • monitoring the impact of any action taken.

2.2. Historical Background pharmacovigilence

Several disasters led to an awareness that drugs not only can heal but also can harm including sudden death caused by chloroform anaesthesia in 1877 and fatal hepatic necrosis due to arsenicals in 1922. In the United States a tragic mistake in the formulation of a children’s syrup in the late 1930s was the trigger for setting up the product authorisation system under the Food and Drug Administration (FDA). FDA had the authority to review new drugs for safety, by scrutinizing animal studies and small human volunteer trials for any signs of serious hazards. Child deaths after diethylenglycol was mistakenly used to solubilise sulphanilamides in 1937 led to the first enactment of legislation on adverse reactions. Following 100 deaths in France in 1952 after diethyl tin diodide and the thalidomide tragedy of the 1960s, in England and in Germany with reports of foetal abnormalities (phocomelia and micromelia) in relation with the use of a new sleep-inducing thalidomide, there was a rapid increase in laws, regulations and guidelines for reporting and evaluating the data on safety, quality and efficacy of new medicinal products. In the summer of 1962 a new bill amending the 1938 Food, Drug and Cosmetic Act, the Kefauver-Harris Amendments, gave the FDA the power to approve or disallow the introduction of new drugs and the continued marketing of established compounds based on substantial evidence of their therapeutic efficacy as well as safety. Around 1980 it became compulsory to record side effects (adverse drug reactions) by the regulatory authorities in many countries to allow for a continual monitoring of the risk and benefit of products both in the investigational phase before authorization and as postmarketing surveillance when the product is commercialised as an authorized product. The consequences of this are that over the last 30 years there have been continued instances of drug recalls or precautionary statements due to the discovery of potential hazards during their use, some more notable examples include: practolol and the mucocutaneous syndrome, benoxaprofen and hepatic disorders / deaths in the elderly, temafloxacin and haemolytic anaemia, fenfluramine/phentermine and valvulopathy or pulmonary

hypertension, terfenadine or cisapride and potential cardiac arrhythmias (especially in association with interacting agents), cerivastatin (Lipobay) and rhabdomyolysis, Vioxx with increased risk of cardiovascular events.


Key Events resulting in Laws and Regulations of pharmacovigilence

1820 Physicians concerned about the quality of domestic and imported drugs convened the first U.S. Pharmacopeia (USP) convention. This convention wrote guidelines for the formulation of drug products, resulting in the publication of the U.S.P. which contains information about drugs including source, physical and chemical properties, tests for purity and identify, assay method of storage, category and dosage 1848 The Import Drugs Act of 1848 allowed U.S. Customs officials to inspect shipments of imported drugs. This function was later assumed by federal agents of the Bureau of Chemistry (renamed the FDA in 1930) 1877 Sudden death caused by chloroform anaesthesia 1898 The Bayer Company sold heroin as “a superior cough suppressant”

1906 Pure Food and Drugs Act of 1906: Problems with medicines and foods outraged the public and Congress. Required manufacturers to list ingredients contained in their products, meet standards of strength and purity established in the U.S.P. Amended over next 30 years to make labeling drugs with false claims a crime and to require physicians to have a license number to prescribe narcotics 1911 In Germany evaluation of marketed medicines was the responsibility of the Congress of Internal Medicine later known as Medicines Commission of the German Medical Profession (Gurwitz et al., 2003).  

2.3 Pharmacovigilance involve

Monitoring of pharmaceutical products and their effects over time identification of possible risks and adverse effects analysis of medical information to track effects informing the public and healthcare professionals of this information

2.4. Institution of Pharmacovigilance practice

There are many organizations in the U.S. and the international community that have pharmacoviligance programs designed to monitor drug use statistics, identify risks and adverse effects, and educate the medical, scientific and lay communities regarding drug safety to best protect the health of patients. Some of these organizations include:

  • WHO
  • International Society of Pharmacovigliance
  • FDA

2.5. Epidemiological studies of pharmacovigilance

During the last decade pharmacoepidemiology, the study of the use and effects of drugs in large populations , has emerged as a developing discipline and has made important contributions to our understanding of drug safety. A good example of this is the confirmation and quantification of the relation between NSAID treatment and gastrointestinal ulceration and bleeding . Expertise in pharmacoepidemiology is now a must for any research based pharmaceutical company and there has been a substantial growth of know-how in many over the past few years. In addition, many companies have established research collaborations with academic institutions in pharmacoepidemiology.

Pharmacoepidemiological studies are largely based on observational rather than experimental data and have some important methodological problems, particularly confounding and bias. The recent debate about studies with third generation oral contraceptives is a good example of this. It is possible that the observed differences between third generation oral contraceptives as compared with second generation ones are due to confounding or bias or both rather than on real differences although this is still controversial .

There is a general scientific and ethical dilemma in pharmacovigilance, which is related to the major mass media attention that drug risks receive. At what point in time during the evaluation of a potential hazard should information be disseminated? If communication is premature, before a hypothesis has been confirmed, the risk is that patients are deprived of useful medicines. If it is too late, patients may be exposed to unnecessary risks. Obviously, there is no simple answer, each case has to be evaluated separately, taking a great number of factors into account including not only the possible ADR under evaluation, but also the risks with the disorder being treated and the risks with alternative treatments  and inappropriate treatment cessation.

This general dilemma, related to media attention, does not only concern pharmaceutical companies but also regulatory authorities and academic institutions involved in pharmacovigilance. Anyone communicating a possible new risk must now realise that the result may be an immediate global media storm, with wide-ranging consequences. (Jyrkka J et al, 2009).


Pharmacovigilence system studies the long term and short term adverse drug reaction or simply stated- side effects of medicines. Pharmacovigilance system involves collection, monitoring, researching upon, assessing and evaluating information received from health care workers such as doctors, dentists, pharmacists, nurses and other health professionals for understanding the adverse drug reaction. Pharmacovigilance definition includes monitoring of all pharmaceutical drugs and also other medical products including vaccines, X-ray contrast media, traditional and herbal remedies etc. especially when the reaction is unusual, potentially serious or clinically significant.

3.1. To measure the Scientific characteristics

Although now seen as a discipline in its own right, pharmacovigilance is related to a number of scientific disciplines, the most important being clinical medicine, clinical and pre-clinical pharmacology, immunology, toxicology and epidemiology.

The identification and analysis of the safety characteristics of medicines falls into two distinct stages. During the first stage, before marketing, the main methodology is experimental with clinical trials comparing the new treatment to placebo or existing alternative treatments. After introduction of a new medicine into general use, the main safety methodology is observational, i.e. uses data from observation of patients treated in clinical practice rather than from experimental situations. In general, the experimental data are of much higher quality than the observational, with better control of confounding factors. The challenge in pharmacovigilance, therefore, is to analyse and draw well-founded conclusions from observational data collected after marketing. In addition, data from observational epidemiological studies are playing an increasingly important role. (Beer C et al 2011).

3.1.1. Pre-marketing clinical trials

Safety monitoring in clinical trials involves collecting adverse events, laboratory investigations and details of the clinical examination of patients. Pharmacovigilance staff may be involved to varying degrees in all phases of clinical trials, including the planning, execution, data analysis and reporting of safety information. Safety issues from animal pharmacology and toxicology studies, findings in phase I studies, known ADRs with similar drugs, signals from other studies and special patient groups, (e.g. the elderly) need to be addressed. The practice of collecting all adverse events rather than suspected ADRs arose from the failure of clinical trials to detect serious reactions with practolol and after several years experience this is now the approach adopted by companies in most studies. The involvement of pharmacovigilance staff in clinical trials also includes an important responsibility for the expedited reporting of individual cases and safety updates required by the UK Medicines Control Agency (MCA) and other regulatory authorities.

Well conducted clinical trials should be able to identify and characterize common type A (pharmacologically mediated)  ADRs, indicate how these are tolerated by patients, determine a relationship between ADRs and dose or plasma concentration and identify pre-disposing (risk) factors if at all possible. These issues will usually be presented and discussed in an integrated safety analysis and clinical expert report in the Marketing Authorisation Application submitted by the company and will be the basis of ADRs, warnings and precautions included in the prescribing information i.e. Summary of Product Characteristics (SPC) or data sheet.

However, clinical trial programmes before marketing are limited in their power to detect rare, particularly type B (non-pharmacologically mediated) ADRs. This is because of the limited number of patients that are studied before marketing , the frequent exclusion of patients who may be at greater risk e.g. the elderly and those with significant concurrent disease, and the structured nature of clinical trials where drugs are given at specific doses for limited periods of time by experienced investigators. Only with wider experience after marketing during routine clinical practice and possibly in larger studies will the less common ADRs and other ‘at risk’ groups be identified. Post-marketing surveillance (PMS) by companies is therefore essential.

3.1.2. Methods of PMS used by the pharmaceutical industry

The general process is basically that utilised by regulatory authorities and other parties working on drug safety matters. The first step is signal generation, i.e. processes that can identify possible new ADRs. There may then be a period of signal strengthening and in the second step such signals are subjected to hypothesis testing, i.e. processes that determine whether the signal does indeed indicate a new ADR, or whether it is false. Whereas the signal generation process is, in principle, relatively simple if the right systems are in place, the hypothesis testing process is challenging and often time consuming and may require a variety of different approaches. The key problem encountered is ‘signal vs noise’—many adverse events observed in treated patients in the end turn out to be related to factors other than the treatment.

3.1.3. The signal generation process

Signals may be generated through four different methods: spontaneous reporting published case reports, cohort studies and post-marketing clinical trials.

3.1.4. Spontaneous reporting

Recording and reporting clinical observations of a suspected ADR with a marketed drug is known as spontaneous or voluntary reporting. The national system in the UK is the ‘yellow card’ scheme where doctors, dentists, and recently, hospital pharmacists are encouraged to report all suspected reactions to new medicines and serious suspected reactions to established medicines. Pharmaceutical companies also collect and collate such reports with their licensed products [8. Reports to companies often come initially as a question from a prescribing physician or pharmacist to Medical Information or a sales representative about whether a product could be the cause of a patient’s problem. After providing such information, pharmacovigilance staff will seek details of the case to add to the database of reports; this relies on the goodwill and continued interest of reporters. Companies must report suspected ADRs to the MCA and other authorities; some authorities, including MCA, make anonymised data available to licence holders. There is also a move towards electronic exchange of data between authorities and companies.

The culture of reporting varies greatly between countries in terms of the quantity, quality and source of reports. In the UK and Sweden most doctors report directly to the national regulatory authority rather than pharmaceutical companies, although some report to both. In other countries such as Germany and the USA the majority of reports go initially to companies who then report to the authority in that country. The proportion of reports received by companies directly from patients also varies considerably between countries and is highest in the USA.

Spontaneous reporting has advantages in that it is available immediately a new product is marketed, continues indefinitely and covers all patients receiving the drug. It is the most likely method of detecting new, rare ADRs and frequently generates safety signals which need to be examined further. The main limitations are the difficulty in recognising previously unknown reactions, particularly events that are not usually thought of as being ADRs and under-reporting, which is variable, sensitive to reporting stimuli and difficult to quantify. It usually does not confirm hypotheses; although situations exist where spontaneous reporting data alone allow conclusions that a signal indeed represents a true ADR, see ‘using spontaneous reporting data for hypothesis testing’ below.

3.1.5. Published case reports

Publishing case reports of suspected ADRs in medical journals is an established way of alerting others to possible drug hazards. However, it has limitations as only a very small proportion of cases can be published, reports are sometimes poorly documented, publication depends on editorial selection and there is often considerable delay between occurrence and publication. Companies and some regulatory authorities actively monitor the published literature for such reports. This will involve screening key journals where ADRs are described, monitoring publications such as ‘Reactions Weekly’ (ADIS International) and running regular standard searches on databases such as Medline and Excerpta Media. With efficient regulatory and company safety surveillance it is now relatively rare for a new ADR to be signalled primarily through published cases, however, publication of well characterised ADRs still fills an important function in alerting physicians. A more recent development is reports of possible ADRs appearing on the Internet and many companies are still determining how they should best handle them.

3.1.6. Cohort studies

Companies may set up or sponsor prospective, non-interventional cohort type studies either to answer safety questions raised after marketing or as a general hypothesis generating and testing tool to be used as need arises. In the past, company sponsored studies were considered poor at detecting new safety issues mainly because of slow recruitment and lack of control groups. Since 1994 such studies in the UK have been subject to the SAMM (Safety Assessment of Marketed Medicines) guidelines which have ensured a closer dialogue between companies and the MCA. Generally, cohort studies are ineffective as tools for signal generation, mainly because of limitations in size; also data from such studies are subject to the ‘signal vs noise’ problem in the same way as spontaneous reports.

Post-marketing clinical trials

Large randomized clinical trials with wide entry criteria (similar to SPC indications) can be valuable in assessing the safety of marketed products as well as confirming efficacy. Because patients are randomised to different treatments they do not have some of the problems inherent in cohort studies, for instance whether the control group is truly comparable. Companies can choose to set up or sponsor such studies to address particular safety issues. To make them sufficiently large to provide more information than the trials performed for product registration purposes may make them prohibitively expensive, hence a simple protocol and study plan with limited observations is desirable.

3.1.7. The hypothesis testing process

A typical situation in company pharmacovigilance is that a small number of reports have been received, showing that the patients have developed a serious medical condition, e.g. liver function disturbance, convulsions or blood dyscrasia, while receiving a particular product. As much detail as possible on the cases must be obtained and any new cases followed-up rigorously but the hypothesis must be raised that this condition has been caused by the drug, i.e. represents an ADR. For analysis of this question, a number of approaches can be taken, the most common being to use the spontaneous reporting data in a variety of ways. Another is to move into formal epidemiological e.g. case-control studies. Pre-clinical pharmacological and toxicological data and clinical trial experience should also be reviewed. (Hajjar ER et al, 2007).

3.2. To describe the Clinical Practice of Pharmacovigilance

Pharmacology curricula should give a higher priority to the study of the safety of medicines. This would lead to an enhanced awareness of the balance between the benefits and harms of medicines. An integrated approach to therapeutic decision-making might be encouraged. Excessive and irrational drug use contributes to adverse reactions.(54, 55) The misuse of medicines is largely caused by the poor quality and inaccessibility of drug information available to practitioners. These problems are worsened by:

• aggressive and inaccurate marketing and advertizing

• uninformed patient use and their demands for the latest medicines

• lack of accurate drug information.

Indicators of inappropriate drug use can be obtained from spontaneous reports of ADRs. Case examples may serve as useful teaching tools for improving the safe use of medicines. In some countries an overwhelming volume of information (as opposed to effective communication of critical information) can serve as a deterrent to rational use. Medication errors and ADRs are well documented in hospitalized and non-hospitalized patients, and they contribute substantially  to morbidity and mortality. They also contribute to the number of hospital admissions and are known to occur in the community setting. Many are predictable and preventable. This suggests considerable opportunity for minimizing the risks of ADRs through rational use, monitoring and follow-up. Early detection is important, particularly in hospitals where systems for detecting ADRs and medication errors will save lives and money. Such systems might be linked to institutional, regional or national pharmacy and therapeutics committees so that information can be used to educate professional staff in safe drug use. Prospective hospital-based surveillance reduces the risk and severity of ADRs. There is, furthermore, a need to provide health professionals with the skills required to evaluate drug information critically and to decide how the safety profile of a drug (e.g. developed from population data) might be applied to a particular patient. Often, the manufacturer’s product information and promotional materials are the only information available to the practitioner. Evidence-based and comprehensive sources may not be available. Availability of balanced and reliable drug information is likely to improve standards of use and to reduce the frequency of adverse reactions. Information that includes patients’ subjective experiences of adverse reactions would be most useful to patients and to prescribers of medicines. Product safety information, the way it is currently presented, often consists of lists of adverse reactions, perhaps rated in order of frequency, without real description of how these might affect quality of life. Moreover, prescribers should be free to practice without being subjected to the vested interest of manufacturers and any conflict in interest.

There are also other opportunities for integrating pharmacovigilance into clinical practice through training and education. Participation of National Centre staff in continuing education programmes, conferences, scientific publications and e-mail discussion groups all contribute. The National Centre might serve as a teaching base, and as a training centre for medical and pharmacy interns, post-graduate students, pharmacology registrars (residents) and drug information staff. Research in ADRs and pharmacoepidemiology in departments of internal medicine and pharmacology should be encouraged and promoted. In the training of health professionals (64) it is important to develop competence in evaluating and communicating information about benefit, harm, effectiveness and risk to the patient. Difficulties in communication between patients and healthcare providers represent an important and preventable potential source of harm. The following elements are likely to reduce significantly the risks of adverse effects and their severity:

• an adequate drug history of the patient

• rational prescribing and dispensing

• proper counseling

• the provision of clear and understandable drug information.

(Mangoni AA, et al, 2004).

3.2.1. Communication with health professionals

A further strategy for integrating pharmacovigilance into clinical practice is the creation of  open lines of communication and broader collaboration between health professionals and National Centres. For this to happen, National or regional centres need to be situated so that two-way communication between health practitioners and professional staff of the centre is easy. Drug information and poison centres are ideal locations for this purpose, since many poisoning reports and drug information queries are in fact ADRs. The staff of these centres are in an ideal position to support the work of pharmacovigilance. Pharmacovigilance centres should provide ready access to clinical expertise and sharing of resources, including databases. Communication materials developed by drug information and poison centers, including newsletters and other publications, can be utilized for disseminating drug alerts and other drug safety information to the professions. Academic departments and university hospitals have proved effective places for national and regional pharmacovigilance centres for a number of reasons. These include the following:

(i) Pharmacovigilance can readily be linked with experimental and clinical pharmacology, and epidemiology in that environment

(ii) The location makes peer review of adverse reaction reports easier and more efficient, and it provides ready access to hospital specialists in university departments. From such a base, and advisory panel for the National Centre with scientific and medical experts can be created         (iii) The information obtained from spontaneous reports can be incorporated into undergraduate and postgraduate teaching in the health sciences

(iv) Health professionals are likely to feel confident in reporting problems and therapeutic dilemmas to an academic unit with which they are familiar and that they know will consider their reports thoroughly and expertly

(v) Effective medical education strategies such as academic detailing, feedback on individual cases, reminders and soliciting the support of acknowledged experts are most readily achievable under these circumstances.

Clinicians making reports expect ready access to the centre and to specialized advice and feedback. They should be encouraged to publish unusual or interesting case reports without delaying submission of such reports to the National Centre. Newsletters, publications and responses by letter or telephone encourage dialogue with clinicians. Collaboration with professional accreditation bodies and associations, academic institutions, continuing education organizations, third party funders (e.g. managed care institutions, medical insurance companies) and other non-governmental organizations adds to the scope and quality of the work of the National Centre. Linking clinical findings with research and policy Careful study of adverse drug events may identify diagnostic features, syndromes or pathogenic mechanisms. Moreover, clinical, pathological and epidemiological information relating to adverse reactions is necessary for a full understanding of the nature of an adverse reaction and for identifying patients at risk. Although spontaneous reporting is the mainstay of passive surveillance, the information obtained is inherently limited and likely to be insufficient for regulatory and clinical decisions. Active or intensive surveillance programmes  for addressing serious safety concerns have had success in identifying and quantifying drug safety issues, using:

• case control networks

• hospital-based intensive monitoring systems

• record linkage systems

• epidemiological studies.

Information received from pharmacovigilance centres should feed directly into drug policy and drug utilization practice. Safety information from National Centres has a bearing on essential drugs programmes, standard treatment guidelines, and national and institutional formularies. Measuring the impact of such information on drug utilization and on the quality of patient care has considerable research potential. It is necessary that drug regulatory decisions should be based on safety information that reflects national as well as international experience, and that this has been thoroughly and expertly reviewed. Drug utilization patterns also need to be taken into account. ADRs have the potential to provide insights into structure-activity relationships, pharmacokinetic, pharmacodynamic and genetic factors affecting the action of medicines. They may provide leads for other novel, indications. This is why it is important for the negative connotation of an ADR to be removed and for systems to be developed that enable medical, pharmaceutical and chemical information to be applied constructively to a better understanding of how drugs work.

3.3. To measure the national drug regulatory authority

The limitations of pre-marketing drug safety data are well-recognized They are aggravated by increasing pressure on drug regulators from the pharmaceutical industry to shorten the review time for new medicines. Registration approval of a new drug is likely to be followed by robust marketing and rapid exposures of thousands even millions of patients to it. The implications for drug safety of this evolving situation need to be addressed.

Pharmacovigilance has become an essential component of drug regulation.(41) For the foreseeable future in developing countries, this is likely to take the conventional form of spontaneous monitoring, even though it is a far from perfect system. Many developing countries do not have rudimentary systems in place for the purpose, and even where pharmacovigilance systems do exist, active support and participation among health professionals, regulators and administrators is likely to be lacking. Underreporting of ADRs by healthcare professionals remains a major problem in all countries. Within the national drug regulatory authority post-marketing surveillance is normally understood to serve a distinct function, separate from the process of evaluation and approval of new medicines. Post-marketing surveillance draws on its own special sources of information, infrastructure and expertise, although there is good reason for these systems and resources to be shared with other disciplines.

Safety monitoring of medicines in common use should be an integral part of clinical practice. The degree to which clinicians are informed about the principles of pharmacovigilance, and practise according to them, has a large impact on health care quality. Education and training of health professionals in drug safety, exchange of information between national Centers, the co-ordination of such exchange, and linking clinical experience of drug safety with research and health policy, all serve to enhance effective patient care. National programmes for pharmacovigilance are perfectly placed for identifying research necessary for better understanding and treatment of drug-induced diseases.

Pharmacovigilance is an activity that has international significance. The current global network of pharmacovigilance Centers, co-ordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider contentious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries.

The Erice Declaration provides a framework of values and practice for collection, analysis and subsequent communication of drug safety issues. In providing for this, it asserts scientific and clinical issues on the one hand and the right of the public to be openly and fully informed on the other. It is a process that requires the active commitment of all involved – regulators, policy makers, health personnel, journalists, and (not least) pharmaceutical manufacturers. Scrupulous attention is required in the practice of pharmacovigilance to the issues of patient confidentiality.

(Mangoni AA, et al, 2004).

3.4 . To describe the Pharmacovigilance in pediatrics

3.4.1. Background and Introduction

There are two very humane behaviours adults have, which can or have resulted in poor outcomes for children. The first behaviour is to give children medicines that have been developed for adults. Denying children a therapy, because it has not been studied in children or has not been produced or marketed in a form which children can or will ingest, is not reasonable. Therefore, any therapy that becomes available for adults is likely to be used for the same or similar conditions in children, even when we have not studied the product in children, may not have a sound scientific basis for establishing a dose (besides scaling down the dose on a weight basis), and have no understanding of how children may react differently than adults to the therapy. The second humane behavior is to protect our children from unknown and uncertain situations. This has also included ‘protecting’ them from research even when the research may provide a potentially better therapy or access to a therapy not otherwise available. As a result, the 20th century is replete with tragic stories of therapeutic misadventures involving children. By the end of the 20th century, children had essentially been left behind in the amazing pharmacologic advances of that era. In addition, if children are not studied in clinical trials, the adverse events defined during the trial are limited to adults. Therefore, most products do not have information on specific pediatric adverse events noted even though the product may be used extensively in the pediatric population. The impetus for the formation of the United States Food and Drug Administration (FDA) has much to do with pediatric therapeutic disasters. The 1938 Federal Food, drug and cosmetic (FD&C) Act was passed after ethylene glycol, a solvent, and raspberry syrup, a sweet-tasting flavouring , were used by the manufacturers chemist in an effort to market an elixir of sulfanilamide.3 The solvent caused renal failure, and many children died because of the chemist’s efforts to provide a needed antibiotic to children in a formulation they would take. This Act required demonstration of the safe use of a new drug product before marketing. The 1962 Kefauver amendments to the FD&C Act required that a product be proven not only safe but effective for the labelled indication. 4 The amendment was partially a response to the thalidomide disaster. Although thalidomide was safe for the mother who took the product, it caused severe limb abnormalities (phocomelia) in the fetus. Another pediatric therapeutic disaster occurred when chloramphenicol therapy caused toxicity and deaths in infants (i.e., grey baby syndrome). This occurred because physicians were not aware that neonates and infants were unable to metabolize chloramphenicol adequately. These examples, which demonstrate the lack of pediatric-appropriate preparations, knowledge regarding teratogenicity, or the understanding of the need for appropriate dosing modifications in certain pediatric subpopulations, highlight the problems which still exist today. Despite urging, in 1977 and 1995 from the American Academy of Pediatrics, that the continued use of untested therapies in the pediatric population was essentially unethical, as it subjected children to a never-ending experiment where little was learned, most products continued to be developed and studied only in adults. Few studies were being performed to answer the dosing and safety issues associated with pediatric use of a product.

(Mangoni AA, et al, 2004).

3.4.2. Necessary of safety reporting

In addition to reasons outlined in other chapters of book as to why some safety issues are not identified until after a product has been approved and on the market (post market), there are seven aspects of pediatric drug development and use which contribute to the probability a safety signal may not be identified in the pediatric population until post marketing.

1. The first of these aspects is the relatively small number of pediatric patients who are often involved in pediatric trials. There are fewer patients affected with pediatric diseases or conditions and trial designs reflect this pragmatic recognition of what is reasonable to expect versus what may be ideal.

2. Children are less frequently involved in early phase 1 pharmacokinetic and safety and phase 2 dose finding and safety studies. This means development of larger phase 3 pediatric trials may be based on information obtained in adults and some pharmacokinetic studies in pediatrics.

3. There is intrinsic variation that exists across pediatric age groups. Product development programs in pediatrics specifically focus on attempting to identify appropriate changes in dosing due to differences in absorption, metabolism, distribution and elimination in the various pediatric age groups. As a result of these differences, one subpopulation of pediatrics may be more or less likely to experience higher levels and/or differences in response to a therapy. Again, because the numbers become very limited when dealing with a subpopulation in pediatrics, it becomes even more difficult to ascertain the real frequency of an adverse event prior to its use in a larger post marketing population.

4. There is extensive off-label use of products within the pediatric population. This off-label use encompasses both use in pediatric subgroups which have not been studied for an indication obtained in one pediatric subgroup, and for other indications which have not been studied in any or most pediatric subgroups, but are marketed for adults.

5. Children have unique exposures through pre-natal (in-utero exposure) and breast milk. Breast-milk exposures are not routinely evaluated for effects on the child. Animal models are utilized to attempt to determine teratogenicity of a product but have limitations as to identification of long-term outcomes not associated with being a teratogen. (Mangoni AA, et al, 2004).

3.4.3 Post marketing review

To fulfill its Congressionally mandated requirement that all adverse events reported during the year after a product has received pediatric exclusivity be referred to the Office of Pediatric Therapeutics at the FDA, and a review of the safety reports be publicly presented to the Pediatric Advisory Committee, the FDA has developed a thorough approach for the review and report of pediatric adverse events. The methods for the specific pediatric post exclusivity review include an analysis of all adverse events reported to FDA’s Adverse Event Reporting System (AERS) during the one year after exclusivity was granted to the product. It is important to understand the timing with respect to approval of products for a new pediatric indication, and the new labeling and marketing for the pediatric use. BPCA requires a pediatric-exclusivity determination within the 3 months after submission of the studies. The review of the data to make a decision about efficacy, safety and dosing in the pediatric population takes 6 months (exception, time frame is 10 months if the pediatric data are submitted as part of an NDA). Thus, the action (e.g., approval or non-approval) occurs at least 3 to 4 months after exclusivity is determined. As a consequence, a product may have been on the market for its approved pediatric indication only a few months when its 1-year post-exclusivity anniversary occurs. There may be limited reporting of pediatric adverse events to the AERS system in the 1-year post-exclusivity because of this situation. FDA may also look at all pediatric AEs reported since marketing of the product when there are limited pediatric data in the AERS system for the 1-year post-exclusivity period. An assessment is also made of how much the drug is used in the pediatric population. In addition, published literature, the summaries of the clinical, pharmacology and toxicology reviews, the trials conducted for exclusivity and the product’s labelling are reviewed to prepare a safety analysis for the Pediatric Advisory Committee. There have been situations where the above process has led to more questions. Additional studies of the product which have been submitted to the agency are then reviewed and other known studies which have been conducted but not submitted to the Agency may also be requested for submission and review. Between June of 2003 and November 2005, there have been eight Pediatric Advisory Committee meetings to review the safety analysis of 50 products which have been granted pediatric exclusivity. Twelve therapeutic categories of products have been involved .The reviews for 39 products raised no new concerns that were not already adequately labelled. In four reviews, the committee expressed a desire that additional monitoring occur and an updated analysis be presented to the committee in another 1 to 2 years. This has usually occurred when there were very few reports and the committee thought additional time might provide a better assessment or limited reports had some concerning aspect.

3.4.4. Adverse events

The areas unique to pediatrics which increase the probability a child may experience either an adverse event or have the adverse event remain unrecognized are of four general types:

1. Differences in the disease process and/or physiology of drug disposition because of differences in maturational and developmental stages of the pediatric population.

2. Difficulties in determining an exposure in some earlier stage of childhood which has a delayed effect on later development or maturation.

3. Formulation issues, which may encompass preparations or medication errors because of extemporaneous or compounded preparations, and exposures to excipients not present in adult preparations.

4. Communication or recognition oversights because infants, small children and mentally disabled children may not be able to articulate what is wrong and/or the caretakers assume it is part of the normal maladies that beset childhood development:

a. Differences in disease process and/or drug pharmacokinetics in children: Children, by definition, are growing, maturing, developing and acquiring skills and information. In addition, many enzymatic, endocrine and metabolic systems and processes have yet to be expressed at the time the child is exposed to an infection or develops a condition and is given a therapy. A disease may not manifest itself in the same way in children as in adults. A high fever in children is more frequently associated with benign processes than a high fever in adults; adults are usually much more symptomatic when exposed for the first time to viral infections such a Hepatitis B. Children have high normal levels of hepatic enzymes and lower levels of creatinine than adults. To recognize the untoward effects of a therapy, one must know what is normal and not all physicians and caretakers are aware of all of the differences in pediatric values for various laboratory tests at the different stages of pediatric development. Numerous studies now demonstrate that children at various ages are going to handle a product’s absorption, distribution, metabolism and elimination differently. Trileptal is an example where children younger than 4 years of age have an apparent increased clearance (L/HR/KG) such that they may require twice the dose per body weight compared to adults. There have been a number of products where younger, pre-school children have not cleared a product as rapidly as older children and other products where the younger children have cleared the product more rapidly. Clearly these differences can result in overdosing and an increase in adverse events runderdosing and a failure to resolve the condition or benefit from the product, respectively.

b. Ascertainment of delayed effects of drugs on growth and development: Children are maturing and changing over a time spectrum. It is difficult to know if any deviation from the normal process was going to occur independently of any exposure to a therapy. Children are  unfinished by definition. Attribution of an exposure to a therapy as the cause of a delay/problem in growth, development or cognitive abilities is often difficult. We know a certain percentage of the pediatric population would experience these problems/delays without any exposure to any therapy. It is difficult to ascertain if the child’s problem would have occurred without the exposure, when the ‘baseline’ was not yet established for that particular child. Confounding this issue is the possibility that an exposure in infancy or early childhood may not express the adverse effect until years later when normally some other maturation event, such as puberty, was to occur. Long-term studies are not usual in pediatrics and are very difficult to ‘power’ because there are so many unknowns for each child and there are many exposures occurring over a long duration of time.

3.4.5. Safety signal detection

The ‘pediatric population’ encompasses preterm babies to adult-sized adolescents, and many aspects of drug disposition, efficacy and safety profile differ over this age range, making extrapolation of safety data from adults to the pediatric population very problematic. Although drugs are used off-label, most have little or no pharmacokinetic data to support rational dosing in pediatrics. Even for those drugs that have had formal clinical studies in pediatric patients, the pre-market safety assessments are limited by inadequately powered studies to evaluate safety. Therefore, postmarketing monitoring of drug safety in pediatrics largely falls on careful evaluation of spontaneous reports and when possible data from epidemiologic studies or sponsor conducted phase 4 post-approval studies. Monitoring of postmarketing data has led to the detection of important drug adverse reactions which are unique to pediatrics. Examples include the use of ciprofloxacin in neonates and its effect on teeth,22 valproic acid and liver toxicity,23 isotretinoin and depression/suicide,24 as well as other examples cited elsewhere in the chapter. Continuous monitoring of spontaneous postmarketing reports supplemented by epidemiological data and data from phase 4 studies with a focus on pediatrics is critical to better define the risks of drugs in the pediatric population. A pediatric safety signal may arise when the evaluation of spontaneously reported pediatric adverse drug events includes the following findings:

1. serious and unexpected drug adverse events that are unique to pediatrics, i.e., not described in the approved product labelling;

2. serious drug adverse events that may be related to a labelled event but differ from the labeled event because of:

• greater severity (hepatic necrosis vs. increase in liver enzymes or hepatitis in the labelling);

• greater specificity (cerebra-vascular accidents vs. cerebral thrombo-embolism or cerebral vasculitis).

3. a new high-risk pediatric subgroup for ADRs is detected arising from off-label use for an unstudied pediatric age group or indication. Once a potential safety signal is detected, evaluation of the signal for possible causality is challenged by the limitations of passive reporting systems. Both the numerator (underreporting of adverse events) and the denominator (lack of good national estimates of pediatric drug exposures) are uncertain and usual reporting rates calculated from these data can be misleading and difficult to interpret. The value of these calculations is further reduced by the lack of valid data on background incidence rates against which the calculated reporting rates are compared. Consequently, it is often not possible to measure excess risk unless the reported event of concern has a hard endpoint (e.g., death, liver necrosis) and it has a low background incidence rate in the general pediatric population.

3.5. To monitor the safety of medicinal products

Before a new medicinal product is placed on the market, all available information on its safety and efficacy comes only from clinical trials. The conditions under which patients and medicines are studied may not necessarily reflect the way medicines are used in hospitals or outpatient practices following their placement on the market. At the time  of granting the marketing authorisation, a relatively low number of patients have been exposed to the product for a limited period of time.

Despite intensive research conducted in animals and during clinical trials in humans, some adverse reactions may be identified only after the product is used by a large number of people. For this reason it is very important to monitor the safety of medicinal products also after their marketing – and this is the subject of pharmacovigilance.

Adverse Events & Adverse Reactions

The ICH E2A guideline describes Adverse Events as any “untoward medical occurrence” which happens to either a patient or a subject in a clinical investigation when a pharmaceutical product has been given to that person1. These encompass any signs which are unfavourable and unexpected for the patient or subject, including any abnormal findings from laboratory testing. These could be symptoms or a diseases temporally associated with the use of a medicinal product, and do not have to have been previously associated with that product. Nor do they have to have a known causal relationship with the course of treatment.

ICH E2A characterises Adverse Reactions according to the stage of the medicinal product’s life cycle. If the product has not yet been marketed, Adverse Reactions are any “noxious and unintended responses”1 to the product at any dose. The effect of this classification is to reasonably establish that a relationship between the product and the reaction “cannot be ruled out. Once the product has been placed on the market, “Adverse Reactions” encompass responses which are again “noxious and unintended” but occur at the established routine dosages which have been defined for use in humans to prevent, diagnose, or treat disease or modify “physiological function”1. However, some more recent definitions include responses to doses and uses outside those recommended.

Suspected Adverse Drug Reaction

This term is discussed in ICH E2A and ICH E2D, it covers those events where there is the reasonable possibility the event is a direct result of taking the product. Inevitably most serious drug reactions are treated as being “suspected” rather than “confirmed” since they would need some kind of additional evidence, such as “dechallenge and rechallenge” in order to be confirmed. This would mean the patient would take the drug, have the reaction, then take the drug again to confirm the reaction. Given the serious nature of such reactions, rechallenge  as a test may be unethical, but it may happen in clinical practice.

Suspected Unexpected Serious Adverse Reactions (SUSARs) and Expected Drug Reactions

Before a product is marketed, a Suspected Unexpected Serious Adverse Reaction is any suspected adverse reaction which is serious and is not consistent with the information on adverse reactions made available in the current investigator brochure. Once a product is marketed, unexpected reactions are reactions which are those not consistent with the statements on adverse reactions included in the standard product information (“labeling”, package insert or Summary of Product Characteristics), although the investigator brochure could also be the reference document for post-marketing studies.

The goal within pharmacovigilance is to protect patients and the public wherever possible and to disseminate knowledge among the relevant professional communities and to patients in order to minimise risk. The information here is provided as a general introduction to the topics and in no way constitutes legal, safety or any other form of professional advice. (Beer C et al 2011).

3.6. To describe the drug regulation

Sound drug regulatory arrangements provide the foundation for a national ethos of drug safety, and for public confidence in medicines. The issues with which drug regulatory authorities have to contend besides the approval of new medicines, include:

• clinical trials

• safety of complementary and traditional medicines, vaccines and biological medicines

• developing lines of communication between all parties with an interest in drug safety and ensuring that they are open and able to function efficiently, particularly at times of crisis.

Pharmacovigilance programmes need strong links with regulators to ensure that authorities are well briefed on safety issues in everyday practice that may be relevant to future regulatory action. Regulators understand that pharmacovigilance plays a specialized and pivotal role in ensuring ongoing safety of medicinal products. Pharmacovigilance programmes need to be adequately supported to achieve their objectives.

A new medicine must pass three hurdles before its approval by the national drug regulatory authority. Sufficient evidence is required to show the new drug to be

• of good quality,

• effective, and

• safe for the purpose or purposes for which it is proposed.

Whereas the first two criteria must be met before any consideration can be given to approval, the issue of safety is less certain. Safety is not absolute, and it can be judged only in relation to efficacy, requiring judgement on the part of the regulators in deciding on acceptable limits of safety. There is a possibility that rare yet serious adverse events (such as those occurring with a frequency of, say, one in five thousand) will not be detected in the pre-registration development of the drug. For example, fatal blood dyscrasia occurring in 1 in 5,000 patients treated with a new drug is only likely to be recognized after 15,000 patients have been treated and observed, provided that the background incidence of such a reaction is zero or a causal association with the drug is clear.a Clinical trial regulation . In recent years there has been a substantial increase in the number of clinical trials in developed and developing countries. Clinical trials in the United States of America alone nearly doubled between 1990 and 1998.(17) With sequencing of the human genome, clinical research in potential new drug therapies is likely to increase even further. aa This arbitrary ‘rule of three’ is based on the experience that for any given adverse effect approximately threefold the number of patients need to be treated and observed for the side effect to become manifest and reliably linked with the drug assuming a background incidence of zero of the effect being observed.

There is also a growing alliance between academia and the pharmaceutical and biotechnology industries. This has given rise to serious and widespread concern over ethical and scientific issues such as:

• the potential for conflict of interest

• unethical patient recruitment practices

• inadequacy of informed consent

• lack of capacity to ensure on-going monitoring of clinical trials and adherence to principles of sound and ethical clinical practice

• poor reporting and management of adverse events.

For drug regulators, the changing trends over recent years in the conduct of clinical trials present special and urgent challenges, particularly in ensuring that the rights and health of patients and their communities are protected. In their approval of clinical trials, regulatory bodies look at safety and efficacy of new products under investigation. They must also pay attention to the general standards of care and safety of study subjects, in conjunction with the appropriate institutional review boards (IRBs). Medicines that are required for diseases such as tuberculosis, malaria, HIV/AIDS and meningococcus A meningitis, and those which may have a questionable or uncertain

effectiveness – safety profile, require careful surveillance when first introduced on a large scale into communities. The increasing complexity of clinical trials presents further challenges to regulators. Study designs often require large cohorts of participants. In many instances trials are carried out at various sites in several countries. Local ethics committees and drug regulators are not always aware of patients’ and investigators’ experiences at other international sites. Clinical trials are increasingly contracted to clinical research organizations and patient recruitment agencies, which act as intermediaries between the sponsors of the study, the investigators and the patients. Responsibility for ensuring proper conduct of the clinical trial may, in such circumstances, be divided between the parties. Information requested by ethics committees and regulators may be difficult to obtain in a short time. Regulators and ethics committees do not always have the capacity to carry out these functions effectively. This may have serious implications for the safety of patients. Safety monitoring during clinical trials is now recognized as one of the major concerns for new drug development. This is currently being addressed by a CIOMS working group. Three main topics are being addressed:

1) the collection of adverse experience information

2) assessment/monitoring of clinical data

3) reporting/communication of clinical data.

A standardized reporting system for safety concerns arising during clinical trials might serve as a helpful tool for regulatory agencies, and for ethics committees (institutional review boards), provided there were full exchange of information between them and the investigators and sponsors. Expedited electronic submission of safety reports in ICH countries has facilitated the reporting process to some extent; however, routine review of safety information requires considerable resources, expertise, support and commitment from those involved. Once research into new drugs is in the post-marketing stage (Phase IV studies) safety may be monitored to comply with the conditions of registration, particularly when there are unresolved concerns. This may lead to improved and more rapid changes in labelling or even withdrawal of a new drug from the market. Routine application of principles of good clinical practice that ensure patient safety and strict compliance with prescribed regulatory requirements would substantially improve standards of clinical trials.  Post-marketing safety monitoring It is now generally accepted that part of the process of evaluating drug safety needs to happen in the post-marketing (approval) phase, if important innovations are not to be lost in an unduly restrictive regulatory net. Judgement as to whether and how this might happen lies with the regulators. The stronger the national system of pharmacovigilance and ADR reporting, the more likely it is that reasonable regulatory decisions will be made for the early release of new drugs with the promise of therapeutic advances. Legislation governing the regulatory process in most countries allows for conditions to be placed on approvals, such as a requirement that there should be detailed pharmacovigilance in the early years after a drug’s release. Careful safety monitoring is not confined, however, to new drugs or to significant therapeutic advances. It has an important role to play in the introduction of generic medicines, and in review of the safety profile of older medicines already available, where new safety issues may have arisen. In a developing country, these latter considerations are likely to be more important than the benefits a novel therapeutic entity might bring to an already pressed health service. While spontaneous reporting remains a cornerstone of pharmacovigilance in the regulatory environment, and is indispensable for signal detection, the need for more active surveillance has also become increasingly clear. Without information on utilization and on the extent of consumption, spontaneous reports do not make it possible to determine the frequency of an ADR attributable to a product, or its safety in relation to a comparator. More systematic and robust epidemiological methods that take into account the limitations of spontaneous reporting are required to address these important safety questions. They need to be incorporated into post-marketing surveillance programmes. There are other aspects of drug safety that have been rather neglected until now, which should be included in monitoring latent and long-term effects of medicines. These include:

• detection of drug interactions

• measuring the environmental burden of medicines used in large populations

• assessing the contribution of ‘inactive’ ingredients (excipients) to the safety profile

• systems for comparing safety profiles of similar medicines

• surveillance of the adverse effects on human health of drug residues in animals, e.g. antibiotics and hormones. (Jyrkka J et al, 2009)

3.7. To describe the Importance of Pharmacovigilance

When a pharmaceutical drug is introduced in the market there are still a lot of things that are unknown about the safety of the new drugs. These medicines are used by various patients for different diseases These people might be using several other drugs and must be following different traditions and diets which may adversely affect the impact of medicine in them. Also the different brands of same medicine might differ in the manner of their production and ingredients. Additionally, adverse drug reactions might also occur when drugs are taken along with traditional and herbal medicines that has also to be monitored through pharmacovigilance. In some cases, adverse drug reaction of certain medicines might occur only in one country’s or region’s citizens. To prevent all undue physical, mental and financial suffering by patients, pharmacovigilance proves to be an important monitoring system for the safety of medicines in a country with the support of doctors, pharmacists, nurses and other health professionals of the country. (Onder G et al, 2005).


Information from many sources is used for pharmacovigilance. These include: spontaneous adverse drug reaction (ADR) reporting schemes, for example, the Yellow Card Scheme clinical and epidemiological studies worldwide published medical literature pharmaceutical companies worldwide regulatory authorities morbidity and mortality databases. Other information sources are used to confirm, characterise and assess the frequency of the reported adverse reactions. Information from all of these sources is carefully screened and may identify unexpected side effects, indicate that certain side effects occur more commonly than previously believed, or that some patients are more susceptible to some effects than others. Such findings can lead to changes in the marketing authorisation of the medicine, such as: restrictions in use changes in the specified dose of the medicine introduction of specific warnings of side-effects in the product information.

4.1. Sources of information in pharmacovigilance

Pharmacovigilance uses information from many sources:

  • Spontaneous reporting of adverse reactions from healthcare professionals (link to adverse reactions)
  • Clinical trials and epidemiological studies
  • Published global medical literature
  • Pharmaceutical companies
  • Healthcare and population statistics
  • Information on the consumption of medicinal products

4.2. Using spontaneous reporting data for hypothesis testing

It is commonplace in clinical practice to make decisions and take actions based on assessment of causality between an event and a certain drug in individual cases. General pharmacovigilance experience however, is that determination of causality in individual cases has a high degree of uncertainty. Attempts to develop the methodology for causality assessment, e.g. by using a Bayesian approach have yielded interesting results but has so far had little impact. Some exceptions to this uncertainty exist, however, for instance the situation of positive rechallenge , i.e. that symptoms and objective findings, having disappeared following discontinuation of the treatment, reoccur on renewed exposure. The other situation is when the adverse event in several patients shows a very consistent pattern both in symptomatology and in relation to the duration of treatment before symptoms, e.g. zimeldine and Guillain-Barre syndrome .

These points illustrate an important similarity between clinical medicine and pharmacovigilance—there is no substitute for careful observation and analysis of single cases. In special situations, various biochemical markers or pharmacokinetic data in individual patients may also contribute to judgments regarding whether observed symptoms or disorders constitute an ADR.

Sometimes, spontaneous reporting data can be used for comparing frequencies of a certain event in a treated population with background incidence of that event. This may be especially possible for rare conditions, like blood dyscrasias. Although there is a high degree of under-reporting, if the reporting rate for a certain event, which can be regarded as a minimum frequency, clearly exceeds the expected frequency, this raises a strong suspicion about a causal relationship. This is a relatively rare occurrence partly because for many conditions reliable background incidence data are not available.

In real life, hypothesis testing can be a rather unsophisticated process. A simple approach is that once the number of reported events of a certain type becomes sufficiently great, regulatory authorities and company pharmacovigilance units could take the stance that these numbers probably reflect a true adverse reaction, unless there exists sufficiently convincing evidence for other causative factors. The general attitude in this area is to an increasing extent being influenced by the fear of litigation, especially in the United States. Most companies now take a very cautious attitude and tend, for legal reasons, to include in the prescribing information a number of possible ADRs which may not have been proven to be real. This is gradually having a more detrimental effect on the value of the prescribing information to practising health care professionals. (Onder G et al, 2005).

4.3. Pharmacovigilance and international health

Pharmacovigilance is an activity that has international significance. The current global network of pharmacovigilance centres , co-ordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider contentious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries. The Erice Declaration provides a framework of values and practice for collection, analysis and subsequent communication of drug safety issues. In providing for this, it asserts scientific and clinical issues on the one hand and the right of the public to be openly and fully informed on the other. It is a process that requires the active commitment of all involved – regulators, policy makers, health personnel, journalists, and (not least) pharmaceutical manufacturers. Scrupulous attention is required in the practice of pharmacovigilance to the issues of patient confidentiality.

Until recently, pharmacovigilance has been confined mainly to detection of adverse drug events that were previously either unknown or poorly understood. Its particular purpose was to contribute to a scientific understanding of the safety profile of a rather small number of drugs and to advise national regulatory authorities. In this document it is proposed that pharmacovigilance has the potential to move beyond its previously rather confined limits, and to serve a higher priority within public health. How that might happen is the subject of this chapter. The burden of ADRs on public health Despite the progress in pharmacovigilance that has been made, the burden on public health of ADRs remains significant. Pharmacoeconomic studies on the costs of adverse reactions suggest that governments pay considerable amounts from health budgets towards covering costs associated with them. In most countries the extent of this expenditure has not been measured. The relationship between drug utilization patterns and the frequency of ADRs is poorly understood. However, it has become increasingly clear that the safety profile of medicines is directly linked with socio-political, economic and cultural factors that in turn affect access to medicines, their utilization patterns and public perceptions of them.

4.3.1. Drug utilization    

Drug utilization patterns are a major determinant in drug safety. For instance, the use of injectable medicines is more common in developing countries. The parenteral route is likely to be associated with a high risk of adverse effects when injections are administered by inadequately sterilized equipment or poorly trained personnel. It is estimated that unsafe injection practice may lead to 780,000 to 1.56 million cases of hepatitis B, 250,000 to 500,000 cases of hepatitis C and 50,000 to 100,000 cases of HIV, annually in Africa. Self-medication and the lack of regulatory control measures over the sale of drugs further increase the risk of adverse reactions. The number of drugs in each prescription is highest in developing countries Factors such as illiteracy, concomitant use of traditional medicines, and the continued availability of impure and irrational pharmaceutical preparations contribute further to the risk. Sound drug legislation, policy and an essential drugs programme that includes education of health professionals and patients in rational use of medicines are measures that should ensure better health care in all countries. Pharmacovigilance programmes could learn from the social mobilization practices that have been introduced in programmes for injection safety during immunization. Social mobilization includes the three-pronged approach of:

• increasing public awareness,

• ensuring advocacy for decision-makers, and

• sensitization of health workers.

This encourages a consumer-based demand for safe medicines from a public that is informed about the safety profile of the medicines they use. The incorporation of pharmacovigilance into these activities should ensure that such measures are relevant locally, and that they promote public confidence in the process. A partnership with patients The ready availability of safer and more effective medicines of good quality inspires confidence and trust among patients. Pharmacovigilance is an essential part of the public programmes that underpin the reliable availability of sound medicines and it needs to be understood, supported and promoted at the highest levels. For this to be achieved it is necessary for information about drug safety programmes to be easily available to the public so that the central role of the patient in the rational and safe use of medicines is understood. The public has in recent years increasingly influenced health professionals’ prescribing and patterns of drug use. This influence and greater awareness on the part of the public is attributable in part to the role of the media and Internet. High expectations of all service providers and medical institutions have developed. Available information is not always reliable or scientifically valid. Direct advertizing to the consumer of prescription medicines has become commonplace in many countries. With this information patients feel more able to make their own therapeutic decisions, without assistance from doctor or pharmacist. The result has been increasing selfmedication, licit and illicit sale of medicines over the Internet, and over-prescribing by doctors on patients’ demand. This has had considerable effect on increased prescribing. If variations in the way medicines are used alter their safety profile, then there is a need for research to be conducted into how the process works. It also needs to be determinedhow access to drug information might influence patient safety, including patients’ perception of safety and the level of harm they are prepared to accept for different medicines. The social and cultural aspects of pharmaceutical use and the expectations and concerns of patients need to be further studied. The outcome of such research should make possible a better formulation of policies with a view to reducing patient risk. Public health programmes and responsible media coverage aimed at increasing access to drug information have made it possible for patients in many countries to take greater responsibility for their own health and for the decisions they make, and in the wider involvement of patients in decisions. This is reflected, in the creation of patient charters and patients’ bills of rights, and in the work of patient advocacy groups. For example, patients with HIV/AIDS have been instrumental in creating international awareness of the impact of the disease and in improving access to therapies and communication of the associated risks. It is a welcome development in some places that patients’ concerns are now recognized as having a legitimate part to play at the heart of the decision-making process. Such public health programmes, however, need not focus only on patients but could be used for the benefit of the general public as well. Such awareness-building and educational initiatives should also include children and elderly populations and could be greatly facilitated through partnerships with the media, educational institutions, other governmental and non-governmental organizations. The Erice Declaration The Erice Declaration (1997) represented significant progress in the light of these changes. The Declaration challenges all the players:

• public health administration

• health professionals

• the pharmaceutical industry

• government

• drug regulators

• the media

• consumers

To strive towards the highest ethical, professional and scientific standards in protecting and promoting safe use of medicines. The Declaration urges governments and others involved in determining policies relating to the benefit, harm, effectiveness and risk of medicines to account for what they communicate to the public and patients. It calls for honesty when communicating drug safety information, even when such information may be incomplete and investigations still underway. It further asks that patients be openly informed of the facts, assumptions and uncertainties of the safety profiles of the medicines they use. Some efforts have been made subsequently to achieve the goals formulated at Erice. Many regulatory agencies have websites to keep the public informed of their regulatory decisions and of drug safety concerns. In the Philippines and Australia videos and television programmes on ADRs are used to encourage reporting. Newsletters, bulletins and electronic distribution lists are increasingly used to communicate safety information globally. The WHO has made considerable efforts to train drug regulators and national immunization staff in communicating information to the media on adverse effects following immunization.  There are, however, several challenges facing pharmacovigilance programmes in achieving the aspirations of the Erice Declaration. These include the following:

(i) The difficulties and risks in communicating conflicting or contentious messages to the public. For instance, during the course of immunization programmes, communication of new safety concerns associated with the vaccine(s), or with programmatic errors, may result in a dramatic fall in coverage. Nonetheless, an approach of secrecy in such circumstances is likely to erode public trust and confidence, and it fails to respect the rights of the public to participate in decision making. Not only do facts and figures need to be shared with the public, but also the process by which the data is assessed and how decisions are made should be shared openly.

(ii) Communication between national drug regulatory authorities and national pharmacovigilance centres needs to be improved so that regulatory decisions with possible international implications are rapidly communicated to regulators, to avoid widespread public concern or panic. (Crentsil V et al, 2010).

4.4. Pharmacovigilance plan

For most products, routine pharmacovigilance (i.e., compliance with applicable postmarket

requirements under the FDCA and FDA implementing regulations) is sufficient for postmarketing risk assessment. However, in certain limited instances, unusual safety risks may

become evident before approval or after a product is marketed that could suggest that consideration by the sponsor of a pharmacovigilance plan may be appropriate. A 30 In the vast majority of cases, risk communication that incorporates appropriate language into the product’s

labeling will be adequate for risk minimization. In rare instances, however, a sponsor may consider implementing a RiskMAP. Please refer to the RiskMAP Guidance for a complete discussion of RiskMAP development. pharmacovigilance plan is a plan developed by a sponsor that is focused on detecting new safety risks and/or evaluating already identified safety risks. Specifically, a pharmacovigilance plan describes pharmacovigilance efforts above and beyond routine postmarketing spontaneous reporting, and is designed to enhance and expedite the sponsor’s acquisition of safety information.32 The development of pharmacovigilance plans may be useful at the time of product launch or when a safety risk is identified during product marketing. FDA recommends that a sponsor’s decision to develop a pharmacovigilance plan be based on scientific and logistical factors, including the following:

1. The likelihood that the adverse event represents a potential safety risk;

2. The frequency with which the event occurs (e.g., incidence rate, reporting rate, or

other measures available);

3. The severity of the event;

4. The nature of the population(s) at risk;

5. The range of patients for which the product is indicated (broad range or selected

populations only. (Walsh EK et al 2010).

4.5. Pharmacovigilance and the national drug regulatory authority

The limitations of pre-marketing drug safety data are well-recognized. They are aggravated by increasing pressure on drug regulators from the pharmaceutical industry to shorten the review time for new medicines. Registration approval of a new drug is likely to be followed by robust marketing and rapid exposures of thousands even millions of patients to it. The implications for drug safety of this evolving situation need to be addressed. Pharmacovigilance has become an essential component of drug regulation. For the foreseeable future in developing countries, this is likely to take the conventional form of spontaneous monitoring, even though it is a far from perfect system. Many developing countries do not have rudimentary systems in place for the purpose, and even where pharmacovigilance systems do exist, active support and participation among health Pharmacovigilance in Drug Regulation  professionals, regulators and administrators is likely to be lacking.  (Crentsil V et al, 2010).

4.6. Partners in Pharmacovigilance

A complex and vital relationship exists between a wide range of partners in the practice of drug safety monitoring. Sustained collaboration and commitment are vital if the future challenges in pharmacovigilance are to be met and the discipline is to continue to develop and flourish. These partners must jointly anticipate, understand and respond to the continually increasing demands and expectations of the public, health administrators, policy officials, politicians and health professionals. There is little prospect of this happening in the absence of sound and comprehensive systems that makes such collaboration possible. The partners concerned, and the present constraints under which they function, are described in this chapter. The constraints include training, resources, political support, and most especially scientific infrastructure. Understanding and tackling these would set the scene for future development of the science and practice of pharmacovigilance.

Pharmacovigilance in Drug Regulation

Sound drug regulatory arrangements provide the foundation for a national ethos of drug safety, and for public confidence in medicines. The issues with which drug regulatory authorities have to contend besides the approval of new medicines, include:

• clinical trials

• safety of complementary and traditional medicines, vaccines and biological medicines

• developing lines of communication between all parties with an interest in drug safety and ensuring that they are open and able to function efficiently, particularly at times of crisis. Pharmacovigilance programmes need strong links with regulators to ensure that authorities are well briefed on safety issues in everyday practice that may be relevant to future regulatory action. Regulators understand that pharmacovigilance plays a specialized and pivotal role in ensuring ongoing safety of medicinal products. Pharmacovigilance programmes need to be adequately supported to achieve their objectives. (Walsh EK et al 2010).

4.7. World Health Organisation and Pharmacovigilance

The thalidomide disaster in 1961 awakened a need to regulate pharmacovigilance not only

by the national competent (regulatory) authorities but also over and above this at an international level. The Sixteenth World Health Assembly in 1963 adopted a resolution stressing the need for early action in regard to rapid dissemination of information on adverse drug reactions and led to initiation of the WHO Pilot Research Project for International Drug Monitoring in 1968. The purpose of this was to develop a system, applicable internationally, for detecting previously unknown or poorly understood adverse effects of medicines forming the basis of the practice and science of pharmacovigilance to improve the safe and cost-effective use of medicines by avoiding further disasters in both developed and developing countries in the interests of improved public health. The International Pilot Programme of 1968 was followed by the WHO Programme for International Drug Monitoring now co-ordinated by the Uppsala Monitoring Centre (UMC) in Uppsala, Sweden, with oversight by an international board. The principal function of the Uppsala Monitoring Centre is to manage the international database of adverse drug reaction reports received from participating countries. The Programme has expanded from 10 countries in 1968 to include more than sixty countries with active participation of regional

reporting Centers (housed within hospitals), interest groups, dedicated internal medicine and pharmacology department units, drug and poison information Centers and other nongovernmental organizations. (Crentsil V et al, 2010).

4.8. Communication with healthcare professionals and patients

Communication with healthcare professionals and patients represents an essential element of pharmacovigilance. The public as well as professionals need to be advised of adverse reactions to medicinal products. SÚKL provides information in particular through the following channels:

Updates of texts accompanying products – Summaries of the product characteristics and Package leaflets – if a new adverse reaction has been described.

Letters sent directly to doctors and/or pharmacists which alert them of possible risks associated with the administration of medicinal products

SÚKL website, where safety update reports are published

Publication of information on adverse reactions in the  (if you would like to receive the Adverse Drug Reaction Information newsletter, please contact the Department of Pharmacovigilance.

(Walsh EK et al 2010).

4.9. National and international regulatory requirements

The reporting of safety information from clinical trials and with marketed products by pharmaceutical companies to regulatory authorities has been mandatory for many years but with each national authority having different requirements. Recent attempts have been made to unify reporting under the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) which brings together regulatory authorities and other experts from Europe, USA and Japan. However, despite this and European Directives and Regulations there is still diversity in requirements  and the guidance from the CPMP Pharmacovigilance Working Party is still in preparation.

The current UK requirements for investigational drugs are included in the CTX/CTC guidance and for licensed products are outlined in the MCA publication Medicines Act Information Letter No 87 . For marketed products individual serious suspected reactions (expedited reports) must be sent to MCA within 15 calendar days of receipt by the company. This applies to UK cases and those from all other European member states; for cases originating outside the EU only serious and unexpected cases (those not listed in the SPC) are subject to expedited reporting. Periodic safety updates containing information on a much wider range of reports and other worldwide safety data over a specified time period are also required. Other EU countries have similar requirements but often differ in detail. If the product is being developed or is marketed in the USA there are extensive FDA reporting regulations with strict deadlines that also have to be met.

One feature of the European requirements is that Marketing Authorisation holders i.e. companies, must have a suitably qualified person responsible for pharmacovigilance. Their responsibilities include the establishment and maintenance of a system which ensures that all ADRs reported to company personnel are collected and collated so that they may be accessed at a single point within the community, the preparation of various reports and answering requests for the provision of additional information from the authorities. Meeting worldwide regulatory reporting requirements is a key business need in pharmacovigilance and companies have invested heavily in staff, computer systems and procedures to meet them. However, this should not overshadow the need for good science and judgement in identifying and analysing important safety issues with products.

Pharmacovigilance is not just about reporting cases to the regulatory authorities, the results of PMS and hypothesis testing should provide useful information which can be communicated to prescribers by updating the SPC/data sheet and Patient Information Leaflet as safety signals are confirmed. Many such updates are initiated by companies although some are imposed by the authorities. The CIOMS III Working Group have compiled a useful commentary and guidance on what core safety information should be available for a product . (Crentsil V et al, 2010).

4.10. Issue and crisis management

Normally, the signal generation and hypothesis testing processes are long-term, and continuous throughout the lifetime of a product, resulting in a gradual build-up of knowledge of the safety properties. At times, however, the process has to become very much compressed in time, resulting in a crisis. This may be because a safety signal implies the possibility of a new and important risk, but actions from regulatory authorities and/or mass media activities may also trigger such situations.

The most important characteristic of the crisis situation is shortage of time. A possible serious hazard for patients, the imminent threat of regulatory actions or mass media pressures calls for rapid actions. At the same time there is a need for analysis of all available data, consultations with experts of various kinds, internal discussion within the company, information to various parties and other activities. This situation is normally handled by a task force, where pharmacovigilance expertise is an important part. Typically, a task force has to produce an analysis of all available data, consult with experts, handle internal and external information and, in the end, make considered benefit-risk judgements and propose actions to be taken. This kind of work is the real test of expertise in pharmacovigilance—to work under extreme internal and external pressures against very short timelines. (Walsh EK et al 2010).

4.11. The future

Pharmacovigilance in the industry will continue to grow and develop as a discipline. In the past, pharmacovigilance units have spent substantial proportions of their time reporting single cases to regulatory authorities around the world, fulfilling widely different local requirements. Current developments promise that this aspect will be gradually simplified. The strong development towards international harmonisation will result in much more uniform international requirements and the very rapid developments in electronic communication will allow automated distribution of case reports within companies and to regulatory authorities.

The future focus of pharmacovigilance work will, therefore, be on the science more than on the formal regulatory aspects, although these, obviously, will continue to be important. Developing and using tools from, for instance, epidemiology and health economics will allow much better judgements of the real impact of treatments on public health and the costs of health care. This fits well with the increasing demand from governments, health care providers and institutional buyers regarding documentation of real benefits of treatments with acceptable risk profiles. The challenge to those working in pharmacovigilance will therefore be to investigate and document, in epidemiological and health economic terms, whether drug safety profiles obtained from clinical trials in narrowly selected populations still hold true when drugs are used in clinical practice. In addition, the identification of possible rare but serious ADRs, and possible actions to prevent them or minimise their negative impact, will continue to be key tasks. (Walsh EK et al 2010).

4.12. The role of pharmacovigilance

4.12.1. In risk management

Risk assessment during product development should be conducted in a thorough and rigorous

manner; however, it is impossible to identify all safety concerns during clinical trials. Once a

product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical

products. Therefore, postmarketing safety data collection and risk assessment based on observational data are critical for evaluating and characterizing a product’s risk profile and for

making informed decisions on risk minimization. This guidance document focuses on pharmacovigilance activities in the post-approval period. This guidance uses the term pharmacovigilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. This includes the use of pharmacoepidemiologic studies. These activities are undertaken with the goal of identifying adverse events and understanding, to the extent possible, their nature, frequency, and potential risk factors. Pharmacovigilance principally involves the identification and evaluation of safety signals. In this guidance document, safety signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product’s use. Signals can arise from postmarketing data and other sources, such as preclinical data and events associated with other products in the same pharmacologic class. It is possible that even a single welldocumented case report can be viewed as a signal, particularly if the report describes a positive rechallenge or if the event is extremely rare in the absence of drug use. Signals generally

indicate the need for further investigation, which may or may not lead to the conclusion that the

product caused the event. After a signal is identified, it should be further assessed to determine

whether it represents a potential safety risk and whether other action should be taken. (Linjakumpu T et al, 2002).

4.13. Risks and benefits of medicinal products

In order to consider a medicinal product as safe, the anticipated benefits should prevail over any risk of injury arising from the administration of the product. All medicinal products can cause adverse reactions, yet it is important that in most people using the medicine no serious adverse reactions occur. Information on potential adverse reactions and their possible prevention is provided in the summaries of the product characteristics and package leaflets which are available from the SÚKL’s database of medicinal products. (Walsh EK et al 2010).                                                                 

4.14. Qualified’ Person responsible for pharmacovigilance

For the pharmaceutical industry, pharmacovigilance is the post-marketing surveillance of the safety of authorised commercialised medicinal products during their life on the market. It includes safety monitoring and evaluation of suspected adverse drug reactions from phase IV clinical trials, observational non-interventional studies e.g. postmarketing surveillance studies, pharmacoepidemiologic studies, solicited reports from surveys, registries, patient diaries etc., literature sources and spontaneous reports from healthcare professionals and includes assessment of quality complaints. The European Pharmacovigilance Guidelines (Eudralex Volume 9) regulate the responsibilities of the pharmaceutical industry to establish a reliable pharmacovigilance system with continual monitoring of drug safety (including regular literature database searches of e.g. Medline, Embase), prompt reporting to the competent authorities (within 15 days of receipt of information), detection of signals with a timely initiation of a risk

management plan. The pharmacovigilance guideline requires a named “qualified person” with medical qualification or direct access to medical expertise (in Germany, der Stufenplabeauftragter) to organise and coordinate safety procedures and risk management including drug recall within the pharmaceutical firm. Inspections will be initiated by the European Medicines Evaluation Agency (EMEA) to check compliance of the pharmaceutical industry with the pharmacovigilance guidelines (CPMP/PhVWP/1618/01) and with the authority to release warnings, public notices of the offence including the name of the Marketing Authorisation Holder and if appropriate take legal action (penal offence and fines).Competent authorities must co-operate and exchange information with one another. (Linjakumpu T et al, 2002).

4.15. The National Pharmacovigilance Centers

At present, post-marketing surveillance of medicines is mainly co-ordinated by national pharmacovigilance Centers. In collaboration with the UMC the National Centers have achieved a

great deal in:

• collecting and analysing case reports of ADRs

• distinguishing signals from background ‘noise’

• making regulatory decisions based on strengthened signals

• alerting prescribers, manufacturers and the public to new risks of adverse reactions.

The number of National Centers participating in the WHO International Drug Monitoring Programme has increased from 10 in 1968 when the Program started to 67 in 2002. The Centers vary considerably in size, resources, support structure, and scope of activities. Collecting spontaneous reports of suspected ADRs remains their core activity. National Centers have played a significant role in increasing public awareness of drug safety. As a result, pharmacovigilance is increasingly seen as more than a regulatory activity, having also a major part to play in clinical practice and the development of public health policy. This development is partly attributable to the fact that many national and regional Centers are housed within hospitals, medical schools or poison and drug information Centers, rather than within the confines of a drug regulatory authority.(Linjakumpu,Tetal,2002).
4.16. Pharmacovigilance in Different Countries/ Regions

All the regions of the world have their own particular pharmacovigilance system, though based on WHO guidelines.

4.16.1. Pharmacovigilance in Europe

Pharmacovigilance system in Europe is coordinated by the European Medicines Agency (EMA) and conducted by the National Competent Authorities (NCAs). The EMA maintains and develops the pharmacovigilance database comprising all suspected serious adverse drug reactions observed in the European region. Here, the pharmacovigilance system is called EudraVigilance and contains separate but similar databases of human and veterinary reactions.

4.16.2. Pharmacovigilance in United States

Here pharmacovigilance has a multi faceted approach. Three branches of pharmacovigilance in the USA can be defined as the FDA; the pharmaceutical manufacturers; and the academic/non-profit organizations like RADAR and Public Citizen. The US Food and Drug Administration (FDA) receives reports about adverse drug reaction and takes appropriate actions for drug safety.

4.16.3. Pharmacovigilance in India

The Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Govt. of India launched the National Pharmacovigilance Programme (NPP) in November, 2004. The pharmacovigilance in India was based on the WHO recommendations made in the document titled “Safety Monitoring of Medicinal Products: Guidelines for Setting Up and Running a Pharmacovigilance Centre”. The whole country is divided into zones and regions for operational efficiency. CDSCO, New Delhi is at the top of the hierarchy followed by two zonal pharmacovigilance centers, Seth GS Medical College, Mumbai and AIIMS, New Delhi.
To summarize the basic knowledge about pharmacovigilance, it can be said that the information obtained from reports about adverse drug reactions promote drug safety on a local and national level. These reports are entered into the national adverse drug reaction database and analyzed by expert reviewers justifying the whole pharmacovigilance system. (Boult C et al 2009).

4.17. Practical Experience in Teaching Pharmacovigilance

A short course in Pharmacoepidemiology and Pharmacovigilance at the London School of Hygiene and Tropical Medicine was started in 1997, and the tenth course has just begun in 2006. There are only a limited number of university-based examined courses in Europe in which pharmacovigilance is a major component. Another example is a flexible Masters course in Pharmacovigilance taught at the UK University of Hertfordshire, which can have components used to have diploma or certificate courses. This course largely uses external teachers. The London School of Hygiene & Tropical Medicine (LSHTM) is Britain’s national school of public health and a leading postgraduate institution in Europe for public health and tropical medicine. Part of the University of London, the London School is an internationally recognized centre of excellence in public health, international health and tropical medicine with a remarkable depth and breadth of expertise. The LSHTM course is part-time and comprises 190 h (approximately 1 day per week) that are spent as follows: 70 h formal teaching and contact time, 70 h self-directed study and 50 h project work. Formal teaching takes place as three sessions of 3 or 4 days in a week (total 11 days) spread over 5 months. Examinations and a project are used to assess students, and there is a high, but not 100%, pass rate. While LSHTM has a sizable active group of researchers studying adverse effects of medicines (over 30 publications in the last 5 years), the course uses external teachers also. Outside experts, particularly from regulatory agencies and those with industry experience in pharmacovigilance, help teach, and some hold honorary positions in LSHTM. Part of the course covers the historical and legal background of pharmacovigilance and pharmacoepidemiology, pharmacological basis of adverse drug reactions and the application of pharmacoepidemiological principles and methods to practical drug issues. The experience of both teachers and participants seems to have been generally very positive. (Boult C et al 2009).

4.18. Teaching and Learning Pharmacovigilance

There are two closely connected primary dimensions of educational need associated with the field of pharmacovigilance. The principal dimension is that of the clinical practitioner who needs knowledge, understanding and wisdom about effects of pharmaceuticals in their day-to-day healthcare practice. The secondary dimension is that of professionals in the field who must amass and evaluate emerging evidence from broad populations exposed to pharmacotherapies. A vital nexus between these two dimensions is found in the spontaneous adverse drug reaction (ADR) report that, for many years to come, is likely to remain a key element in the intelligence-gathering systems of professional pharmacovigilists. The educational needs of practitioners in each of these fields have considerable interdependency. On the one hand, beyond personal empirical observation, the healthcare practitioner needs to learn to continually discriminate benefits and risks associated with the pharmacotherapies they are supervising. On the other hand, the professional pharmacovigilist needs to develop and maintain the same fundamental clinical knowledge and discriminatory skill as well as mastery of increasingly complex systems of signal generation, systematic investigation of signal meaning and effective communication back to the public and healthcare practitioners. This chapter therefore addresses the educational needs, opportunities and challenges for both groups: characterized here as learners and teachers of pharmacovigilance. In recent years, two significant political undercurrents have powerfully influenced the field of pharmacovigilance: these currents have created a notable undertow that has magnified interest in and extended the scope of teaching in this field. Additionally, these forces have resulted in a more lively interest in the communication of findings from the field of pharmacovigilance to those engaged in overseeing pharmacotherapy in practice. The first of these currents derives from publicity and revitalized public interest in mistakes and mishaps in conventional healthcare provisions. The second has emerged from concerns about medicinal drug therapy, and the contemporary expectation that available therapies should be uniformly ‘safe’ in customary use. Both of these movements will be examined in this chapter. Implications will be discussed for both the individual practitioner’s need to learn pharmacovigilance in the care of their patients and also for training. ( Stahl SM, 1999).

4.19. Clinical trial regulation

In recent years there has been a substantial increase in the number of clinical trials in developed and developing countries. Clinical trials in the United States of America alone nearly doubled between 1990 and 1998. With sequencing of the human genome, clinical research in potential new drug therapies is likely to increase even further.

There is also a growing alliance between academia and the pharmaceutical and biotechnology industries. This has given rise to serious and widespread concern over ethical and scientific issues such as

• the potential for conflict of interest

• unethical patient recruitment practices

• inadequacy of informed consent

• poor reporting and management of adverse events.

( Stahl SM, 1999)


For all medicines there is a trade-off between the benefits and the potential for harm. To minimize the harm, it is necessary that medicines of good quality, safety and efficacy are used rationally, and that the expectations and concerns of the patient are taken into account when therapeutic decisions are made. To achieve, this is to serve public health, and to foster a sense of trust in patients in the medicines they use that would extend to confidence in the health service in general.

The discipline of pharmacovigilance should be developed considerably day by day, and it remains a dynamic clinical and scientific discipline. It has been essential to meet the challenges of the increasing range and potency of medicines (including vaccines), which carry with them an inevitable and sometimes unpredictable potential for harm.

The risk of harm, however, is less when medicines are used by an informed health profession and by patients who themselves understand and share responsibility for their drugs. When adverse effects and toxicity appear – particularly when previously unknown in association with the medicine – it is essential that they should be analyzed and communicated effectively to an audience that has the knowledge to interpret the information. There is a realization that drug safety is more than the monitoring, detection and assessment of ADRs occurring under clearly defined conditions and within a specific dose range. Rather, it is closely linked to the patterns of drug use within society. Problems resulting from: irrational drug use, overdoses,
polypharmacy and interactions, increasing use of traditional and herbal medicines with other medicines, illegal sale of medicines and drugs of abuse over the Internet, increasing self medication practices, substandard medicines, medications errors, lack of efficiency. This is the role of pharmacovigilance.

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