|Year : 2013 | Volume
| Issue : 2 | Page : 126-131
Pharmacovigilance in India
Sarita Mulkalwar, Pratibha S Worlikar, Niranjan Munjal, Lopamudra Behera
Department of Pharmacology, Padmashree. Dr. D.Y. Patil Medical College, Hospital & Research Centre Dr D Y Patil Vidyapeeth, Pimpri, Pune, India
|Date of Web Publication||10-Apr-2013|
CB-26, Clarion Park, Beside Aundh Tel. Exchange, Aundh, Pune - 411 007
Source of Support: None, Conflict of Interest: None
New drug development is a challenging and costly process as it involves focus on quality, efficacy as well as safety. Some of the adverse drug reactions (ADRs) are predicted based upon the previous experience with the pharmacologically similar drugs and others are detected during clinical trials. For detection of ADRs, clinical trials usually provide limited information as they are conducted under strictly controlled condition and largely focus on efficacy evaluation. Some of the ADRs can be detected only after long-term use in large population and in specific patient groups due to specific concomitant medications or disease. The visual field defect of vigabatrin therapy and valve defect of fenfluramine-phenteramine therapy are few such examples. Therefore early recognition of previously unknown adverse effects of medicines during post-marketing period is the primary objective of pharmacovigilance.
Keywords: Adverse drug reactions, pharmacovigilance, spontaneous reporting system
|How to cite this article:|
Mulkalwar S, Worlikar PS, Munjal N, Behera L. Pharmacovigilance in India. Med J DY Patil Univ 2013;6:126-31
| Introduction|| |
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects of a drug or any other possible drug-related problems.
The concept of pharmacovigilance or monitoring of drug safety dates back to much before 150 years, however, findings published in 1893 in The Lancet confirmed for the first time the establishment of a reporting system for suspected adverse drug reactions (ADRs). 
Pharmacovigilance, a French word, was described as "a discipline involving detection, evaluation and prevention of undesirable effects of medicines." This was derived from the Greek "pharmakon" meaning a drug or medicine and from the Latin "vigilans" meaning watchful or careful.  World Health Organization (WHO) defines pharmacovigilance as "the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem." 
The drug development process includes the continuum from the identification of a potential pharmaceutical agent to research on possible efficacy and safety through regulatory approval. The drug approval process mainly involves phase I, II, III (pre-marketing), IV (post-marketing) trials. Pre-marketing studies necessarily take place in controlled situations with selected group of people. Though a new drug appears to be safe in these studies, unseen adverse effects can occur when a drug is released for use in general population. 
| Need for pharmacovigilance|| |
Today, the need for an efficient pharmacovigilance system has been realized more than ever to ensure safe use of drugs. There are multiple reasons for this increasing necessity of pharmacovigilance. Some of these are as follows:
- Unreliability of pre-clinical safety data
- Well-controlled conditions
- Small and specific sample size
- Pressure from various groups to reduce time to approval.
- Changing pharmaceutical marketing strategies
- Aggressive marketing
- Direct advertising to consumer
- Launch in many countries at a time.
- Changing physician's and patient's preferences
- Increasing use of newer drugs
- Increasing use of drugs to improve quality of life
- Shift of supervised to self-administered therapy.
- Easy accessibility
- Increasing conversion of prescription drugs to over the counter drugs
- Easy access to drug information on the Internet
- Easy availability of complementary medicines
- Easy availability of substandard drugs.
Limitations of clinical trials
- Homogeneous population sample
- Strict inclusion/exclusion criteria
- Subjects usually have single disease
- Specific groups of children, elderly and pregnant are excluded.
- Small sample size
- Detection of rare adverse effect is difficult.
- Short duration of trial
- Limits the detection of long-term adverse effects.
- Inability to detect ADRs under real life situations
- Drug interaction
- Drug food interactions
- Large number of other unpredictable conditions
- Detection of risk factors.
The Purpose of Pharmacovigilance
Until recently, pharmacovigilance was mainly concerned with the detection of adverse drug events that were previously either unknown or poorly understood. Its purpose was to contribute to a scientific understanding of the safety profile of drugs and to advice national regulatory authorities.  Recently, the scope of pharmacovigilance has been widened to include: ,,,
- Herbal preparations
- Traditional and complimentary medicines
- Blood products
- Medical devices
Many other issues that are also of relevance to the science of pharmacovigilance include: 
- Substandard medicines
- Medication errors
- Lack of efficacy reports
- Use of medicines for indications that are not approved and for which there is inadequate scientific basis
- Case reports of acute and chronic poisoning
- Assessment of drug related mortality
- Abuse and misuse of medicines
- Adverse interactions of medicines with chemicals, other medicines and food.
Signal detection in pharmacovigilance
Signal generation consists of formulation of a hypothesis suggesting a possible association between exposure to a drug and appearance of ADR. Thus the signal generation is a method highlighting a potential adverse reaction and safety issues related to the use of particular drug that need further investigations. The possibility of new ADR to a medicinal product, i.e., signal generation may be difficult to identify often because most of the adverse drug effects are not new clinical entities and new signal often concerns with new cause of an old disease. A causal relationship between the drug and the adverse reaction is difficult to establish as a particular drug can cause multiple ADR and a particular ADR can cause by multiple drugs.
Signals are usually derived from patient or population groups. Different types of signals require different types of detection methods. Various methods for detection of signal in Pharmacovigilance are mentioned below.
| Pharmacovigilance methods|| |
As per International Conference on Harmonization Efficacy Guideline 2 ICHE2E  guidelines, the pharmacovigilance methods can be categorized as:
- Passive surveillance
- Spontaneous reporting system (SRS)
- Case series
- Stimulated reporting
- Active surveillance
- Sentinel sites
- Drug event monitoring
- Comparative observational studies
- Cross-sectional study (survey)
- Case-control study
- Cohort study
- Targeted clinical investigations
- Descriptive studies
- Natural history of disease
- Drug utilization study
Pharmacovigilance methods can be also classified as hypothesis generation methods and hypothesis testing methods.
Hypothesis generating methods
- Spontaneous ADR reporting
- Prescription event monitoring
Hypothesis testing methods
- Case-control study
- Cohort studies
- Randomized controlled trials.
For practitioners, the most important system for pharmacovigilance is SRS: The SRS is the oldest, most productive and cost-effective method of ADR reporting. The SRS involves the voluntary participation of health professionals, pharmacists, nurses and patients themselves for reporting the observations related to ADR. The health professionals can use the report form to give all relevant data related to the drug and suspected ADR. Experts review the reports on a case-to-case basis and evaluate whether there is a pattern representing the possible signal. Often a single report may not be conclusive and a set of reports from independent observers is required to generate a signal. Further studies will be required to either confirm or disapprove the signal, as it is only a warning and not the actual evidence of possible association.
As the reporting system is voluntary it has some important limitations and the most noticeable is under-reporting. Sometimes the ADRs are not even suspected either due to difficulty in relating the ADR to a drug clinically or because no such reaction has previously been described or because of long time lag between exposure and the event. Besides, the reporting rate is also influenced by a number of other factors such as type of drug, duration for which a drug is available in the market, publicity of the drug, availability in combinations etc. Some degree of under-reporting is unavoidable and the extent of under-reporting is hard to measure. Thus the data generated only on the basis of voluntary reporting cannot be used to estimate the rate of occurrence of suspected ADR and the frequency of ADRs is often underestimated. However, a hypothesis about possible relationship can be formulated for further investigation.
| National pharmacovigilance system - India|| |
In India, Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Government of India, launched the National Pharmacovigilance Programme (NPP) in November 2004. It is largely based on the recommendations made in the WHO document titled "Safety monitoring of medicinal products - Guidelines for setting up and Running a Pharmacovigilance Centre."
The immediate aim of NPP is to foster the culture of ADR notification by health care workers. Subsequently, it seeks to generate broad based ADR data on the Indian population and share this with Uppsala Monitoring Centre (UMC), WHO database. This would ensure optimum safety of drug products in India. 
Under this programme, the 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 centres
- Seth G. S. Medical College, Mumbai for South-West Zone.
- All India Institute of Medical Sciences, New Delhi for North-East Zone.
There are five regional pharmacovigilance centres located:
- Kolkata Institute of Postgraduate Medical Education and Research-Seth Sukhlal Karnani Memorial (IPGMR-SSKM Hospital)
- Mumbai (TN Medical College and B Y L Nair Charitable Hospital)
- Nagpur (Indira Gandhi Medical College)
- Delhi (Lady Hardinge Medical College)
- Pondicherry Jawaharlal Insitute of Postgraduate Medical Education and Research (JIPMER).
Twenty-eight peripheral centres spread across the country (Department of Pharmacology, Pd. Dr. D.Y. Patil Medical College, Pimpri, Pune is one of the peripheral centres).
Flow of ADR reports from health care professional to WHO-UMC is given in [Figure 1].
|Figure 1: Flow of adverse drug reaction reports from peripheral health care professionals to World Health Organization|
Click here to view
As per the WHO -UMC the causality classification of ADRs is as follows. 
Certain: A clinical event including laboratory test abnormality occurring in a plausible time relationship to drug administration and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug should be clinically plausible. The event must be definitive pharmacologically using a satisfactory re-challenge procedure if possible.
Probable: A clinical event including laboratory test abnormality with a reasonable time sequence to administration of the drug unlikely to be attributed to concurrent disease or other drugs or chemicals and which follows a clinically reasonable response on withdrawal (de challenge). Re-challenge information is not required.
Possible: A clinical event including laboratory test abnormality with a reasonable time sequence to administration of the drug but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
Unlikely: A clinical event including laboratory test abnormality with a temporal relationship to drug administration which makes a causal relationship improbable and in which other drugs chemical or underlying disease provide plausible explanation.
Conditional: A clinical event including laboratory test abnormality reported as an adverse reaction about which more data is essential for a proper assessment or the additional data are under examination.
Inaccessible: A report suggesting an adverse reaction which cannot be judged because of insufficient or contradictory information and which cannot be supplemented or verified.
The severity classification of ADRs is as follows: 
Mild/Minor: No antidote therapy or prolongation of hospitalization is required.
Moderate: It requires a change in drug therapy, specific treatment or an increase in hospitalization by at least 1 day.
Severe: Potentially life threatening causing permanent damage or requiring intensive medical care.
The frequency of ADR is calculated on the basis of number of events (numerator) occurring in a particular number of population (denominator). Based on the frequency, ADRs are classified as given in [Table 1]. 
| Adverse drug reactions reporting|| |
Reporting of ADR is done mainly voluntary. ADRs can only be sent by health care workers to any of the nearest pharmacovigilance center. The complete list of these centers is available at www.cdsco.nic.in.
How to report?
ADRs are reported by filling up the ADR form. A reporting form should be distributed to different departments of hospital and institutions, general practitioners etc. in order to collect the ADR data.
A case report in pharmacovigilance must at least contain the information about the adverse reaction seen in a patient, details of the suspected drug including all the other drugs used by the patient and details of the reporter (which is kept confidential and used only for data verification and case follow up). Besides telephone, fax and e-mail are also convenient ways of reporting.
What to report?
For new drugs usually reporting of all suspected adverse reactions is requested. For established drugs, serious or unusual suspected adverse reactions should be reported whereas known and minor reactions are of little interest. ADR associated with herbal medicines should also be reported. Lack of efficacy and other drug-related defects might be reported in case of possible manufacturing defect or counterfeit drugs. Adverse reactions related to the use of cosmetics should also be reported.
Reporting of adverse event during clinical trials is done as per Good Clinical Practice GCP guidelines.
Who will report?
Health care professionals (doctors, dentists, pharmacists, nurses) are the most preferred source of information for collecting the data related to the ADR.
Programme shall not accept reports from lay member who is not a health care professional. Patient can contact his/her family physician in case of suspected ADR.
Drug manufacturers are mainly responsible for safety of their products. During the new drug status period of 4 years, the manufacturer is expected to report any new information about the drug like a new side effect observed, a new drug interaction or even a new clinical use detected by chance discovery. During this new drug status period manufacturer is expected to submit the Periodic Safety Update Report every 6 months during first 2 years and annually for next 2 years.
The problem of under-reporting is faced in almost all the countries.  Apart from the number of reports, the quality of data and the relevance of the case reports are also important.
The reasons for under-reporting are:
- Non-availability of ADR forms
- Fear of risk litigation
- Fear of negative reflection of one's competence
- Doubts regarding the causal role of the drug.
The outcome and impact of current system
NPP and international pharmacovigilance programmes already in place have given encouraging results by identifying potentially dangerous ADRs and steps have been taken in the past by not only taking measures to effectively deal with the ADR but also by withdrawing the potentially harmful drugs from the market  [Table 2].
| Conclusion|| |
Drug safety monitoring is an essential element for effective use of medicines and for high-quality medical care. It has the potential to inspire confidence and trust among patients and health care professionals in medicines and contributes to raising standards of medical care. Besides, ARDs significantly diminish the quality of life, decrease the safety and increasing duration of hospitalization, subsequently increasing the mortality and morbidity. The financial burden on health care authorities increases enormously. As the newer drug treatments are becoming available to the needy at a faster rate due to several recent trends in approval and regulation, the drug-related adverse reactions are also becoming more common, severe and complex. Clearly the formulation and implementation of a highly-efficient pharmacovigilance programme which can meet the required objectives is of prime importance at national and international level.
| References|| |
|1.||Commission on Anaesthetics. Report of the Lancet Commission appointed to investigate the subject of the administration of chloroform and other anaesthetics from a clinical standpoint. Lancet 1893;1:629-38. |
|2.||Evans SJ. Pharmacovigilance: A science or fielding emergencies? Stat Med 2000;19:3199-209. |
|3.||Gupta SK, Moore N, Chatterjee A, Sharma M. Role of pharmacovigilance in clinical research. In: Gupta SK, editor. Drug Discovery and Clinical Research. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2011. p. 280. |
|4.||Lamarque V, Plétan Y. The pharmaceutical industry and the adverse effects of the drugs. Ann Pharm Fr 2007;65:308-14. |
|5.||WHO. Pharmacovigilance and international health. The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products. Geneva: WHO; 2002. p. Gupta SK. Pharmacovigilance: Need and objectives. Textbook of Pharmacovigilance 2 nd Ed. Jaypee Brothers Medical Publishers (P) Ltd. New Delhi; 2011. p.21-7 |
|6.||Meyboom RH, Egberts AC, Gribnau FW, Hekster YA. Pharmacovigilance in perspective. Drug Saf 1999;21:429-47. |
|7.||Abbing HD. Legal aspects of medical devices: Study on regulatory mechanisms for safety control. Health Services Research. Lansdale PA, USA: IOS Press; 1993. p. 358-61. |
|8.||Mehta U, Milstien JB, Duclos P, Folb PI. Developing a national system for dealing with adverse events following immunization. Bull World Health Organ 2000;78:170-7. |
|9.||Chan TY. Monitoring the safety of herbal medicines. Drug Saf 1997;17:209-15. |
|10.||Gupra SK, Surinder S. Pharmacovigilance: Need and Objectives. Textbook of Pharmacovigilance 2 nd Ed. New Delhi; Jaypee Brothers Medical Publishers (P) Ltd.; 2011. p.23 |
|11.||ICH Topic E2E pharmacovigilance planning (PVP) June 2005 CPMP/ICH/5716/03. |
|12.||Adithan C. National pharmacovigilance programme. Indian J Pharmacol 2005;37:347. |
|13.||Gupta SK. Adverse Drug Reaction: Classification, Mechanism, Interaction. Textbook of Pharmacovigilance 2 nd Ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2011.p.39-59 |
|14.||Gregory PJ, Keir KL. Medication misadventures. Adverse drug reactions and medication errors. In: Malone PM, editor. Drug Information: A Guide for Pharmacists. New York: Mc Craw Hill Professional; 2000. p. 487-518. |
|15.||Gupta SK, Singh S. Adverse drug reactions: Classification, mechanism and interaction. In: Textbook on Pharmacovigilance. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2011. p. 39-59. |
|16.||Gupta SK, Singh S. Setting up a Pharmacovigilance center. In: Textbook on Pharmacovigilance. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2011. p. 93-103.17. |
|17.||Gupta SK, Moore N, Chatterjee A, Sharma M. Role of pharmacovigilance in clinical research. In: Gupta SK, editor. Drug Discovery and Clinical Research. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2011. p. 313. |
[Table 1], [Table 2]