INTRODUCTION:

Pharmakon (Greek) = drug, Vigilare (Latin) = to keep watch; awake, alert; watchfulness in respect of care, danger, caution, circumspection; process of paying close and continuous attention. According to the Pharmacovigilance 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, biological, medical devices and vaccines”.

Pharmacovigilance is defined as “the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long-term and short-term adverse effects of medicines”.

· These adverse drug reactions (ADRs) not only add to the suffering of patients but also increase morbidity and mortality along with a financial burden on society. The overall incidence of ADRs in hospitalized patients is estimated to be 6.7% (range 1.2–24.1%) and that of fatal ADRs 0.32% (0.1–0.85%)

· Data indicates that in patients who experience ADRs death rates are 19.18% higher and the length of hospital stay is 8.25% higher. Total medical costs for patients with ADRs are increased by an average of 19.86%.

· However, the lack of ability of clinicians to suspect or detect such adverse events related to drugs might lead to inappropriate management of adverse Events thus exposing the patient to additional drug hazards. To minimize the suffering of the patients from ADRs, it is essential though difficult to establish causal relationship between the drug and the event which Is nothing but the causality assessment. By definition, causality assessment is the evaluation of the likely hood that a particular treatment is the cause of an observed adverse event.

· It assesses the relationship between a drug treatment and the occurrence of an adverse event. It is an important component of pharmacovigilance, contributing to better evaluation of the risk-benefit profiles of medicines and is an essential part of evaluating ADR reports in early warning systems and for regulatory purpose.

Historical Background of Pharmacovigilance:

It was not until 1986 that a formal adverse drug reaction (ADR) monitoring system consisting of 12 regional centers, each covering a population of 50 million, was proposed for India.2 In 1997, India joined hands with the World Health Organization (WHO) Adverse Drug Reaction Monitoring Program based in Uppsala, Sweden^[1]. Three centres for ADR monitoring were identified, mainly based in teaching hospital: A National Pharmacovigilance Centre located in the Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi and two WHO special centres in Mumbai (KEM Hospital) and Aligarh (JLN Hospital, Aligarh Muslim University). These were centre to report ADRs to the drug regulatory authority of India. The major role of the centre was to monitor ADRs to medicines which are marketed in India. However, they hardly functioned as information about the need to report ADRs and about the functions of this monitoring centre were yet to reach the prescribers and there was lack of funding from the government. This attempt was unsuccessful and hence, again from the 1st of January 2005, the WHO- sponsored and World Bank-funded National Pharmacovigilance Program for India was made operational. The National Pharmacovigilance Program established in January 2005, was to be overseen by the National Pharmacovigilance Advisory Committee based in the Central Drugs Standard Control Organization (CDSCO), New Delhi.

The pharmaceutical industry has prime responsibility for the safety of medicines, from the start of drug development and thereafter throughout the lifetime of the drug. Many companies have developed innovative and efficient monitoring systems that have contributed to the detection of new safety signals. Encouraged by the 1998 Erice Declaration on Communicating Drug Safety, communication and exchange of information between the industry, regulatory authorities and the public has improved, which has more recently been further supported by the establishment of the community database (Eudravigilance Database) in December 2001, in London.

Aim of Pharmacovigilence:

Improve patient care and safety in relation to the use of medicines, all medical and Par medical interventions.

· Research the efficacy of drug and by monitoring the adverse effects of drugs right from the lab to the pharmacy and then on for many years.

· Pharmacovigilance keeps track of any drastic effects of drugs.

· Improve public health and safety in relation to the use of medicine.

· Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost effective) use.

· Promote understanding, education, clinical training in pharmacovigilance and its effective communication to the public.

Need of Pharmacovigilance:^[2]

It is widely accepted that clinical development of medicines is a complex process which require huge amount of time for its completion. Once a drug is marketed, it leaves the secure and protected scientific environment of clinical trials and is free for consumption by the general public. At this point, most medicines will only have been tested for short-term safety and efficacy on a limited number of carefully selected individuals. Hence, need of pharmacovigilance arises which include, securing the early detection of new adverse reactions or patients subgroups of exceptional sensitivity; and introducing certain measures in order to manage such risks. Moreover, it is essential that new and medically still evolving treatments are monitored for their effectiveness and safety under real-life conditions after being marketed. Furthermore, more information is generally needed about use in specific population groups like children, pregnant women and the elderly, about the efficacy and safety of chronic use in combination with other drugs. Numbers of adverse effects, drug-interactions and risk factors have been reported later in the years of drug release rational and cost-effective use of drugs; promoting understanding, education and clinical training in pharmacovigilance; and effective communication to the generic public. In addition, providing information to consumers, practitioners and regulators on the effective use of drugs along with designing programs and procedures for collecting and analyzing reports from patients and clinicians conclude to the objectives of pharmacovigilance studies.

Pharmacovigilance in different sectors.:

Fig no.1 Pharmacovigilance in different sectors.

Objectives of Pharmacovigilance:^[3]

The main objectives of pharmacovigilance involve exhibiting the efficacy of drugs by monitoring their adverse effect profile for many years from the lab to the pharmacy; tracking any drastic effects of drugs improving public health and safety in relation to the use of medicines; encouraging the safe, rational and cost-effective use of drugs; promoting understanding, education and clinical training in pharmacovigilance; and effective communication to the generic public. In addition, providing information to consumers, practitioners and regulators on the effective use of drugs along with designing programs and procedures for collecting and analyzing reports from patients and clinicians conclude to the objectives of pharmacovigilance studies.

· Improve patient care and safety in relation to the use of medicines and all medical and Para medical interventions.

· Research the efficacy of drug and by monitoring the adverse effects of drugs right from the lab to the pharmacy and then on for many years.

· Pharmacovigilance keeps track of any drastic effects of drugs.

· Improve public health and safety in relation to the use of medicines.

· Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use.

· Promote understanding, education and clinical training in pharmacovigilance.

Roles of Pharmacovigilance:

The role of pharmacovigilance is to check the 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. Pharmacovigilance approve the drug regulatory authorities’ needs to go further than the approval of new medicines, to encompass a wider range of issues relating to the safety of medicines, namely:^[4-5]

· Clinical trials;

· The safety of complementary and traditional medicines, vaccines and biological medicines;

· The receipt, processing and reporting of adverse event reports;

· Following-up with reporters to obtain further details about a case report;

· Providing an information service to healthcare professionals and patients on product safety; and providing safety expertise to internal cross-functional colleagues.

Pharmacovigilance programmes need to maintain strong links with the drug regulatory authorities to ensure that the latter are well briefed on safety issues in everyday clinical practice, whether these issues are relevant to future regulatory action or to concerns that emerge in the public domain. On the other, regulators need to understand the specialized and pivotal role that pharmacovigilance plays in ensuring the ongoing safety of medicinal products.

Good pharmacovigilance Practices:

Risk assessment and risk minimization form what FDA calls risk management. It is an iterative process of ^[6]

· Assessing a product’s benefit-risk balance

· Developing and implementing tools to minimize its risks

· Evaluating tool effectiveness and reassessing the benefit-risk balance

· Making adjustments as appropriate to the risk minimization tools to further improve the benefit risk balance.

This four part process should be continuous throughout a product’s lifecycle with the results of risk assessment informing the sponsor’s decisions regarding risk minimization. The Federal Food Drug and Cosmetic Act (FDCA) and FDA implementing regulations establish requirements for routine risk assessment and risk minimization (e.g., FDA requirements for Professional labeling and adverse event monitoring and reporting.

Adverse Drug Monitoring:^[7]

Adverse drug reactions (ADRs) are common, often unrecognized and typically under-reported however, update knowledge and skills related to detection, assessment, prevention, management and transparent notification / reporting of ADR is essential for an efficient Pharmacovigilance everywhere on the globe.

ADR is defined as “any response to a drug that is noxious and unintended and that occurs in man at doses for prophylaxis, diagnosis, or therapy, including: new, rare, or previously poorly documented reactions”.

ADR Includes:

1. ADRs associated with newly marketed medications.

2. Serious, life-threatening, or fatal reactions.

3. According to the Food and Drug Administration, a serious adverse event is one in which the patient outcome is death, life-threatening), disability, hospitalization (initial or prolonged), a congenital anomaly, or necessitates medical or surgical intervention to prevent permanent impairment or damage.

4. Unusual increases in numbers or severity of reactions.

5. Allergic reactions and idiosyncratic reactions are also considered ADRs, if they are deemed to be serious, life threatening, or fatal, as described above.

However, the definition of ADR shall not include:

a) Adverse effects of the drug which are related to the size of the dose, expected, well-known reactions and do not result in changing the care of the patient.

b) Drug withdrawal, drug-abuse syndromes, accidental poisoning, and drug-overdose complications (e.g., drowsiness from diphenhydramine).

c) Reactions which are extensions of the pharmacologic effect for which the drug is given (e.g., bone marrow suppression with antineoplastic agents).

d) Disturbances totally dependent on the pathological state (e.g., diarrhoea from cancer and not from a laxative).

Some types of ADRs:

Serious Adverse Event (SAE):

An adverse drug reaction or adverse event that Results in death or is life threatening or requires in-patient hospitalization or prolongation of existing hospitalization or Results in persistent or significant disability or incapacity, or Causes congenital.

Fig. 2 chart for Adverse Events

Unexpected Serious Adverse Drug Reaction-A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator’s brochure or on the label of the drug. Expected Adverse Reaction-An adverse reaction identified in regulatory documents such as the Investigators Brochure or Product Monograph occurring within the expected frequency estimate; or identified in the Research Ethics Board (REB) submission and letter of information to participants; or is related to study intervention and was the result of the natural progression of the person’s disease/illness and/or state of health. Related to the Drug or Research Intervention: There is a reasonable possibility that the reaction or event may have been caused by the drug or research intervention (i.e. a causal relationship between the reaction and the drug or research intervention cannot be ruled out by the investigator).

A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an adverse reaction that is both serious and unexpected (i.e. the nature and severity Absence of ADRs and freedom from unintended, unwanted negative or excessive effects of drugs.

Classical examples of serious and unexpected adverse reactions:

1. Aminophenazone- aggranulocytosis.

2. Chlormphenicol- Aplastic anemia

3. Methyldopa-Haemoltic anaemia

4. Oral contraceptive-Thromboebolisam

5. Reserpine-depresssion.

6. Thalidomide-congenital malformation.

CLINICAL TRIALS^{[8,
9, 10, 11]}

Pharmaceutical companies are required by law in all countries to perform clinical trials, testing new drugs on people before they are made generally available. The manufacturers or their agents usually select a representative sample of patients for whom the drug is designed at most a few thousand along with a comparable control group. The control group may receive a placebo and/or another drug that is already marketed for the diseases. Clinical trials do, in general, tell us a good deal about how well a drug works and what potential harm it may cause. Clinical trials, also known as clinical studies, are designed to help us find out how to give a new treatment safely and effectively to people. A clinical trial is an organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease and attempt to improve a patient’s quality of life. The first clinical trial of a novel therapy conducted by Renaissance surgeon Ambroise Pare in 1537; used a concoction of turpentine, rose oil and egg yolk to prevent the infection of battlefield wounds. The first known controlled clinical trial was carried out by James Lind; documented citrus fruits in the diet could prevent scurvy. Clinical trials are performed to find out if new drugs are safe and how well they work, and also to see if drugs would be effective for other conditions. There are mainly 4 types of clinical trials, such as treatment trials, prevention trials, screening trials, and quality of life trials. These trials also allow clinical researchers to have access of potentially life-saving therapies to patients with serious conditions. Mainly 4 phases of clinical trials are

Phase I:

In this phase, primarily provide information on acute tolerability and safety, dose-plasma concentration profiles, maximum safe doses and concentrations, routes of metabolism and elimination and initial estimates of the variability associated with these measurements.

Phase II:

In this phase, establish clinical efficacy and incidence of side effects in patient population define most appropriate dose schedule and provide detailed pharmacological date for optimum use of the drug.

Phase III:

In this phase, check whether the treatment is effective, compare it with available and established treatment, and determine optimum dosage, frequency of administration, use fullness of drug in patients, safety of treatment and common adverse reactions of the compound.

Phase IV:

In this phase, designed to reveal adverse reactions related to prolonged usage, drug efficacy in long term use, new uses, an assessment of misuse or overuse liability, drug interactions and compatibility with other agents. There are certain steps and protocols, which needed to be followed while caring out the actual clinical trials. Today FDA’S main aim is, by using new diagnostic, imaging, and clinical evaluation techniques, to bring new drugs and medical products in market. These new "toolkit" include advances in basic sciences such as in bioinformatics, genomics, and imaging technologies. These technologies make drug discovery and development cheaper, faster, and more predictable. Apart from the technologies, new advances are emerging in clinical trials. Some of them are - Model-based drug development offers significant opportunity to improve drug development decision-making. Clinical Trial Modeling and Simulations observations regarding pharmacological actions is embedded in mathematical equations and set of assumptions embedded in a mathematical equation and give “virtual” information about the analysis of the pharmacological observations of patients.

PHARMACOEPIDEMIOLOGIC STUDY^[12-14]

Pharmacoepidemiology is defined as “the study of effects of and use of drugs in large populations. It is the use of epidemiological methods to address issues from clinical pharmacology, usually questions about the balance between beneficial and adverse effect of drugs.” It also takes into account patient compliance and other factors that apply when drug is used under real-life conditions. They are not experimental but observational in nature. Pharmacoepidemiologic studies can be of various designs, including cohort (prospective or retrospective), case-control, nested case-control, case-crossover, or other models.

Cohort study:

Cohort study compares exposed to unexposed patients and evaluates differences in outcome over time. In a cohort study, a population-at-risk for the disease (or event) is followed over time for the occurrence of the disease (or event). Information on exposure status is known throughout the follow-up period for each patient. A patient might be exposed to a drug at one time during follow-up, but non-exposed at another time point. Since the population exposure during follow-up is known, incidence rates can be calculated. In many cohort studies involving drug exposure, comparison cohorts of interest are selected on the basis of drug use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events can also be investigated using the same data source in a cohort study. However, it can be difficult to recruit sufficient numbers of patients who are exposed to a drug of interest (such as an orphan drug) or to study very rare outcomes. Like case-control studies, the identification of patients for cohort studies can come from large automated databases or from data collected specifically for the study at hand. In addition, cohort studies can be used to examine safety issues in special populations (the elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if sufficient numbers of patients exist.

Fig 4. Cohort study.

Case control study:

This compares individual with disease to individual without disease. In a case-control study, case of disease (or events) are identified. Controls, or patients without the disease or event of interest, are then selected from the source population that gave rise to the cases. The controls should be selected in such a way that the prevalence of exposure among the controls represents the prevalence of exposure in the source population. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease in the two groups. Patients can be identified from an existing database or using data collected specifically for the purpose of the study of interest. If safety information is sought for special populations, the cases and controls can be stratified according to the population of interest (the elderly, children, pregnant women, etc.). For rare adverse events, existing large population-based databases are a useful and efficient means of providing needed drug exposure and medical outcome data in a relatively short period of time. Case-control studies are particularly useful when the goal is to investigate whether there is an association between a drug (or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse events. Risk factors can include conditions such as renal and hepatic disfunction that might modify the relationship between the drug exposure and the adverse event. Under specific conditions, a case-control study can provide the absolute incidence rate of the event. If all cases of interest (or a well-defined fraction of cases) in the attachment area are captured and the fraction of controls from the source population is known, an incidence rate can be calculated.

Fig.5. Case control study

Case Report:

In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence. Some case reports also contain a literature review of other reported cases. FDA recommends that sponsors make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events and encourages sponsors to use trained health care practitioners to query reporters. Good case reports include the following elements:

· Description of the adverse event

· Suspected and concomitant product therapy details

· Patient characteristics

· Documentation of the diagnosis of the events

· Clinical course of the event and patient outcomes

CONCLUSION:

It nearly takes a billion dollars to develop a drug. With so many drugs every year facing scrutiny, the three major regulatory agencies including the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMEA), and Medicines and Healthcare products Regulatory Agency (MHRA) have started the publication of Drug Safety News Letters to keep our medical community posted - including physicians, dentists, nurses, and pharmacists - about selected post marketing drug safety reviews, important emerging drug safety issues, and recently approved pharmaceutical products. Pharmacovigilance is not easy, and its errors and problems are repeated. Of course, by proactively detecting signals and with better risk management plans, some of the questions may be answered. However, without proper educational training in this field and good work experience it is difficult t o understand the intricacies that are involved and what to look for.

Pharmacovigilance required for systematically identifying and correlating drugs and side-effects and taking corrective actions, especially for the product launching first time in India. Pharmacovigilance is the only way to ensure the safety of drug throughout the lifecycle. Its importance is very much crucial as the clinical trials have limitation to detect the rare and very rare ADRs. If all the healthcare professionals take ADR reporting as ethical obligations and their major responsibilities, we can make our world safer than what is today. Every reporting by healthcare professionals is important; even though, focus on the serious unlabselled type of ADRs is more important. There are significant efforts on the pharmacovigilance to make it more functional after the concept has emerged, and day by day we are closer to the destiny. It is our responsibilities to ensure phamacovigilance system is functioning well. ADR reporting should be taken as a very important duty; not as an extra clinical burden; by healthcare professions to ensure the safer drug use throughout the world.

ACKNOWLEDGEMENT:

Authors are highly Acknowledge the help of teaching staff of Rajarambapu College of Pharmacy, Kasegaon. For providing necessary information required for research work. Also we are highly Acknowledge the help and guidance of Dr. Mangesh A. Bhutkar.

REFERENCES:

1. The importance of Pharmacovigilance, Safety Monitoring of Medicinal Products. WHO 2002, the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring 2002, 52.

2. http://www.haiweb.org/19072009/19Jul2009IssueFactSheetPharmacovigilance

3. WHO, Safety of medicines in public health programmes: pharmacovigilance an essential tool, WHO 2006.

4. Phillips KA, Veenstra DL, Oren E, Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review, JAMA, 2001, 4:2270-2279.

5. Goldstein DB, Pharmacogenetics in the laboratory and the clinic, N Engl J Med, 2003, 6:553-556.

6. WHO [1995] safety monitoring of medicinal products. Guidelines for good clinical practice [GCP], for trails on pharmaceutical products, Geneva.

7. Pir Mohamed –M, breckenirdge AM, Ktteringgham NR, et.al adverse drug reactions. BMJ 1998; 316 (7140):1295-8.

8. http://imaginis.com/breasthealth/clinical_trials.asp Phase of pharmacovigilance Pharmacovigilance: Ensuring the Safe Use of Medicines - WHO Policy Perspectives on Medicines, No. 009, October 2004apps. who. int

9. http://www.healthandage.com

10. Bhat P, Velingkar VS, Drug Discovery- A General Overview, Indian journal pharm education, 37(2),2003,94-99.

11. Ted Agres: FDA: New tools cut a critical path, Drug Discovery and Development, 2004, Available at http://www keepindia.com.

12. http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm.

13. WHO, Pharmacovigilance: ensuring the safe use of medicines, Geneva: WHO 2004

14. U.S. FDA, Guidance for Industry Good Phramacovigilance Practices. and Pharmacoepidemiologic Assessment, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Rockville, MD, March 2005.

Received on 20.03.2019 Accepted on 15.04.2019

Asian J. Pharm. Res. 2019; 9(2): 116-122.

DOI: 10.5958/2231-5691.2019.00019.4