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A pharmaceutical drug undergoes various phases of the drug development process to assess its safety and efficacy, before entering the market. Clinical trials capture only short term data on the drug action and adverse effects since they are conducted in highly controlled settings. Pharmacovigilance is a practice aimed to monitor drug safety in real life conditions and capture adverse drug events during the post marketing phase of its life cycle. But under reporting of adverse reactions of the drug is a major cause of concern and a threat to the pharmacovigilance system. As per available scientific literature, the major obstacles to under reporting are inadequate knowledge and awareness among health professionals, clinicians’ perceptions towards reporting, problems with establishing pharmacovigilance systems in hospitals and insufficient training to recognize ADRs. Lack of ADR data can result in possible signals being missed, which would lead to unsafe drugs being marketed for human consumption. Some measures to improve the situation include involvement of nurses, pharmacists as well as consumers in the reporting of ADRs, making the process easier and faster through electronic means, introducing educational interventions and training programs for health care providers and spreading awareness about the reporting system amongst caregivers and receivers alike. Providing a momentum to the pharmacovigilance system and ensuring a robust reporting process is a challenge but proper planning, feasible solutions and focussed efforts can help bring about the change, making healthcare a better experience for the patients.
Every pharmaceutical drug that enters the market is expected to have some adverse effects when used by patients outside clinical trial settings. It is quintessential for both the consumers as well as health care professionals to detect those ill effects that can further be used to generate “warnings” regarding unexpected drug associated events and establish its safety. The reason why is it crucial to monitor the adverse reactions to drugs when their profile has already been studied and assessed before they are put to commercial use is the need to make the drugs safer. Clinical development process involves at most few thousand carefully selected patients exposed to the test drug for a short duration, and is conducted under test tube like situation including protocolized care and strict monitoring. This is contrary to a real life, pragmatic situation wherein the drug could be consumed by the elderly and young alike and the adverse effects of long term use of the drug, along with drug-drug interactions can be captured. Clinical trials miss the lesser common ADRs occurring with a frequency of 0.5 to 1% and cannot entirely capture the more common ones. (1)
An Adverse Drug Reaction (ADR) as defined by the WHO is a “response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.” (2)
Due to these evident drawbacks, it is essential to monitor and report ADRs consistently throughout the duration of use of a medicine in a population, to evaluate if the risks outweigh the benefits, detect ADRs early, predict their frequency and ensure safe and efficacious use of medicines.
Post authorization, a significant amount of the information on drug safety is acquired through ‘pharmacovigilance’, a practice aimed primarily at protecting public from serious and unusual adverse events. According to the World Health Organization, pharmacovigilance is defined as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.”
The scope of pharmacovigilance now includes herbals, traditional medicines, blood products, biologicals, vaccines and medical devices as well. The International Drug Monitoring programme was launched by WHO after the thalidomide incident that occurred in the early 60s. Pharmacovigilance is promoted by the WHO through its Collaborating centre at Uppsala and aims to enhance patient safety, and provide relevant and reliable information for the risk-benefit assessment of marketed drugs. (3)
As per findings from the Centre for Health Policy Research, the number of approved drugs in the U.S. associated with adverse reactions that go undetected during trials is about 50%. (4)Studies have shown that ADRs occur in about 10-20% of hospitalized patients, with their overall incidence being around 6.7% and that of fatal ADRs around 0.32%. They are the 4th to 6th largest cause of mortality in the U.S.(5)
According to Centre for Disease Control, about 40% of ambulatory ADRs are preventable and this is a huge concern worldwide.(6)
A recent study that assessed the prevalence of ADRs internationally showed that the proportion of inpatient hospitalizations due to an adverse reaction was 2.3%, 4.8% and 7.3% for England, Germany and the U.S. respectively.(7)Another study concluded that around 3% to 7% of hospital admissions can be attributed to adverse drug reactions. (8)The percentage of outpatients with ADRs ranges from 5% to 35% all age groups in the U.S.(9)The cost of ADRs borne by hospitals in the US is nearly S$4 billion annually.(4)
THE INDIAN SCENARIO
Studies conducted in several parts of India have estimated the incidence of suspected ADRs to be around 2% to 3% among hospitalized patients. (10)(11)(12)
Results from a study carried out at a referral centre in South India showed that out of all hospital admissions, 0.7% were attributed to ADRs and 1.8% of ADR related admissions resulted in deaths.(13)A study conducted by Doshi et al. showed that the average cost of managing ADRs was in excess of 1000 INR per patient, with the total cost of preventable ADRs as high as Rs 96000 which was about 64% of the total cost of all ADRs.(12)This highlights the critical economic impact of adverse drug reactions and their management. ADRs increase the length of hospital stay, add to treatment costs and are a burden on the healthcare system of a country. Most ADRs are preventable if the drugs are used rationally and it is very unfortunate that they still increase the healthcare costs by many folds.
The number of adverse drug reactions is likely to increase in future because new drugs are being introduced often at expedited timelines, more and more drugs are being prescribed, and there is no formal well established system of monitoring of ADRs.(1)
Spontaneous reporting is the most commonly used form of reporting ADRs by health professionals, and in many countries, by patients themselves. Spontaneous reporting is voluntary and involves an alert health professional or patient linking an adverse reaction to the use of a particular drug and reporting it to an ADR Monitoring Centre (AMC). This system of reporting provides the largest amount of information in a highly cost effective manner. It helps in early identification of signals which can be followed by more in-depth investigations and even regulatory warnings and amendments to patient information leaflets. (14) Individual Case Safety Reports (ICSRs)are collectively sent across to the National Centre periodically which is responsible for sending them to the WHO centre in Uppsala, for processing, identification and analysis of new signals for adverse reactions associated with the particular drugs.(15)
Thus, spontaneous reporting serves as the preliminary step for generation of “signals” against particular drugs. According to the WHO, a signal is “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.” Thus, signals are like hypotheses based on data provided through spontaneous reporting. They are uncertain but instrumental in drawing attention to various complications that might be drug induced, like its effect in high risk groups and dosage issues. (16)
Vigilant clinicians on encountering ADRs among their patients can voluntarily report them. One such example of spontaneous reporting is published case reports. A very critical issue with this form of monitoring is under reporting. (1)A systematic review done in the UK to estimate the extent of under reporting of ADRs from available literature showed the median rate of under reporting as high as 95%, with not much difference between reporting rates from hospitals and general practice. (17)
Focussing specifically on India, the government launched a national pharmacovigilance program, called the Pharmacovigilance Program of India (PvPI) in 2010,to safeguard the health of the people of the country and ensure that the benefits of the medications consumed, outweigh their risks. PvPI is theNational Coordination Centre for pharmacovigilance activities that assists the Central Drugs Standard Control Organization (CDSCO) to make decisions regarding the safe and effective use of medicines.(18)
India has nearly 150 ADR monitoring centres (AMCs) in various medical colleges across the country. AMCs play a pivotal role in collection of ADR information from the patients and send completed reports to the NCC. NCC further sends the data to the Uppsala Monitoring Centre, Sweden.(19)There is a significant lack of reports generated from the AMCs and India’s contribution to the global database of WHO-UMC is just about 2%. (20) Also, the Indian Pharmacovigilance Programme is still in its infancy. The ADR reporting rate in India is just about 1% compared to 5% worldwide. (21)In spite of the establishment of 150 AMCs, the AMC functional rate is just around 56%. (22)
In this review, we aimed to investigate the shortcomings associated with Spontaneous reporting in India, the lacunae that need to be filled and the possible solutions worked out globally, to improve this kind of monitoring.
An open search for relevant articles was undertaken in MEDLINE (the Pubmed database) and google search using key words like “pharmacovigilance”, “spontaneous reporting”, “ADR reporting”, “adverse drug reaction reporting”, “under reporting of ADRs”, “spontaneous ADR reporting system” and “India”; with their corresponding MeSH terms if any, joined by OR or AND operators where applicable. Also, the articles obtained from the reference list of the preliminary search were used to further gather relevant articles using what is referred to as the snow ball technique. The search was not limited to a specific time period. No search filters were used but the articles were limited to the ones published in English Language.
KNOWLEDGE AND AWARENESS REGARDING ADR REPORTING: THE ACTUAL SCENARIO
According to global statistics, the ADR reporting rates are the highest for the high income countries and lowest for the low income countries. Also, there is considerable variation in these statistics among countries in each income group. (23)Studies conducted in various medical colleges in India have revealed the significant unmet need for ADR reporting. The knowledge and awareness among Indian prescribers with respect to spontaneous reporting of ADRs and pharmacovigilance as a whole is suboptimal. Their attitudes and beliefs towards reporting of ADRs are a cause of concern as well.
Awareness about Pharmacovigilance and ADRs: One study revealed that only two-thirds of the clinicians could define an ADR correctly, only one one-third of them could correctly define pharmacovigilance and all of them felt the need of a pharmacovigilance programme in India, having little idea about the existence of one. (24)
In another study, less than 10% of the prescribers were aware of the Uppsala Monitoring Centre of the WHO and familiarity with the Naranjo Algorithm as the Causality Assessment tool was also reported to be low. The proportion of clinicians aware of what should be reported was as low as 10%. Not even half of them were aware that ADRs could also be identified during the Phase 4 of a clinical trial and that spontaneous reporting was a tool to monitor adverse reactions of newly introduced drugs. (25) Less than 20% of them knew that serious ADRs need to be reported with 14 calendar days. (25)(26)
Clinicians across studies felt that ADR reporting was very necessary (25)(27) but only 50-75% of them were aware that such systems were already in place. (24)(25)(28)(29)(30)
Most health care practitioners had no idea as to where and how should an ADR be reported (26)(29) and about half of them were not familiar with the process at all. (31)A majority of the resident doctors participating in a survey had no idea that even suspected interactions among drugs and ADRs without an evident cause required the same amount of vigilance. (30)About a third of the prescribers enrolled in another study were unaware of the types of ADR reactions or the thalidomide tragedy. (28)
The awareness among doctors, that even nurses, physiotherapists and pharmacists could report ADRs, according to a study, was 70%, 30% and 40% respectively. (30)
In studies conducted among the pharmacists, the proportion aware of the term ADR was found to be more than 90% but only half of them were aware of the pharmacovigilance system and its inception in India. Almost all pharmacists knew that they were obliged to report ADRs but only 50% of them knew what type of ADRs should be reported. (32)
Among the medical post graduate students too, the proportion aware of pharmacovigilance and ADRs was just around 65%. (33)
Attitudes, Beliefs and Practices: Findings from a few studies showed that a majority of clinicians believed only ADRs to new drugs should be reported, and only about two-thirds believed that ADR reporting is a professional duty they are obliged to fulfil. (25) Most of them had witnessed ADRs in their patients (25)(34) and had seen the reporting form (25) and yet only less than a third had ever reported an ADR themselves to the ADR monitoring centres. (24)(25)(27)(29)(31)(35)(36) Almost half of the medical practitioners in a survey, felt that we needed more monitoring centres. (31)
One study showed that the proportion of resident doctors reporting adverse reactions to the national centres was as low as 3%. (30)Many clinicians believed it was not necessary to report adverse reactions that were already well recognized and known. (26) Also, about 50% of the prescribers in a survey were of the perception that only serious ADRs were expected to be reported. (27)In one study, more than 80% of the physicians in a hospital reported having suspected/witnessed ADRs without reporting them. (36)One interesting finding from a survey showed that the majority of clinicians at a tertiary care teaching hospital in India felt that ADR reporting was just confined to Allopathic medicines and hence did not pay attention to other forms of medications. (29)(30)
About 5% of pharmacists also believed that all drugs are supposedly safe, around 16% of them felt that herbal drugs do not cause any ADRs. Almost 6% of them thought that even if they do, such ADRs do not need to be reported. (32)
Data from a study conducted on medical interns showed that less than 50% reported the adverse reactions they observed. Out of them, about 30% reported the ADRs to their heads of departments, about 10% to the ADR monitoring committee and as less as 4% actually reported them to the pharmacovigilance centre. (34)
Another study conducted in Madhya Pradesh demonstrated that the gap between the number of
ADRs experienced and the frequency of reporting them, was huge, especially among dentists who had hardly reported an ADR in their career. (37)The fact that just about 50% of the clinicians had ever received any training on ADR reporting raises an alarm too. (25)(34)
OBSTACLES TO REPORTING OF ADVERSE REACTIONS: FACTORS ASSOCIATED WITH UNDER REPORTING
The review of available data from India highlighted some critical barriers that hinder the spontaneous reporting of adverse drug reactions, tabulated below.
|S.No.||Obstacles/Barriers to reporting||Description|
|1.||Clinicians’ perceptions regarding ADR reporting||
|2.||Gaps in knowledge and inadequate training||
|3.||Issues with potential conflicts||
|4.||Problems with organizing the pharmacovigilance system at hospitals and among consumers||
|5.||Attitude of health care professionals towards ADR reporting||
SOLUTIONS TO UNDER REPORTING: FILLING THE LACUNAE
Inadequacy in reporting of ADRs leads to lack of ADR data that are submitted to the WHO Pharmacovigilance centre which ultimately can result in many probable signals being missed or unduly delayed in being captured. Until the spontaneous reporting system is strengthened, we cannot appropriately ensure the safety of the drugs marketed for human consumption.
Some measures that can be undertaken to improve the spontaneous system of adverse event reporting in India are:
|S.No.||Solutions to under reporting||Description|
|1.||Involvement of nurses and pharmacists in reporting of ADRs:||
|2.||Making the reporting process easier, more convenient and less time consuming:||
the hyperlink was included. (48)
|3.||Educational interventions and training for health care professionals and medical students:||
|4.||Tools to enhance the pharmacovigilance system and encourage reporting among clinicians:||
|5.||Including patients/consumers as reporters of adverse reactions:||
|6.||Improving the forms for spontaneous reporting of ADRs:||
|7.||Focussing on reporting of paediatric and geriatric ADRs:||
Severe ADRs are a major cause of morbidity in children and around 95% of them go unreported.
THE WAY FORWARD FOR INDIA
In an attempt to facilitate ADR reporting by patients/consumers, the PvPI launched a toll free helpline facility in 2014, to encourage the general public to report any adverse reaction that could possibly be associated with a drug they consume. A majority of the population is still unaware about this helpline system reiterating the fact that the PvPI needs to take measures to promote the pharmacovigilance system in our country.(60)
Towards the end of 2015, a mobile application was launched, to provide a platform for private healthcare professionals to promptly report ADRs. While it is a commendable initiative, it needs to be expanded to government hospitals and practitioners through initiatives like awareness campaigns, since they handle an enormous number of patients every day. Also, coming up with a similar application for consumers would definitely add to the number of reports being submitted through the helpline.
Establishing a robust system of reporting of ADRs and providing a momentum to the pharmacovigilance systems to grow is a challenge. It is an uphill task that can only be completed through paying close attention to the short comings, planning meticulously to overcome them, and coming up with solutions that are meaningful, cost effective and feasible in the Indian scenario where the patient inflow is huge and the health care professionals are overburdened. Attempts to change the mindset first, by imparting knowledge & increasing awareness, followed by slow yet significant changes in practice and the general attitude, can make way for a more reliable pharmacovigilance system that is well equipped to not just handle ADRs but deal with them appropriately for the betterment of patients as well as the community at large.
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