1. INTRODUCTION:

Drug safety, more commonly referred Pharmacovigilance, is the vibrant clinical and scientific discipline¹. During clinical trial new drug is placed for safety and efficacy assessment in humans in very controlled conditions and limited number of subjects, so after launching of drug in real time world where these conditions and limitations repealed, there is a possibility that drug can act differently in patients with concomitant co morbid conditions with polypharmacy or in long term use, in respect to safety.

Hence the process of studying these safety concerns after post marketing is called pharmacovigilance. World Health Organization (WHO) has defined this process in concise manner as a ‘science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem². Pharmacovigilance is now the activity of contributing protection of patient and public health through providing timely information about safety of drugs to patient, healthcare professionals and public³. However, WHO also brought safety of herbal and traditional medicines, biological and medical devices under the radar of pharmacovigilance⁴. In the past, detecting adverse effect and to report it to the drug makers or regulators was the long process without maintaining timeliness^5,6. Now, under the stringent regulations from regulatory authorities of different countries concerning safety of marketed drugs and globalization of pharmaceutical and biotechnological companies across world, this field is growing enormously and currently evolved in to multibillion dollar business since its proactive inception after thalidomide tragedy and newer technologies have replaced the conventional pharmacovigilance system.

2. HISTORY OF PHARMACOVIGILANCE:

When we call it a history of pharmacovigilance, it should be divided in to two parts. Pre-thalidomide tragedy pharmacovigilance and post thalidomide tragedy pharmacovigilance. Thalidomide tragedy was the event which leads to inception of modern pharmacovigilance. A normal antiemetic pill resulted in to the disastrous adverse reaction in new born babies in the form of characteristic feature of shortness of limbs called phocomelia, when these pills were taken by pregnant women for morning sickness in late 1950s to early 1960s.

2.1 Pre-Thalidomide Tragedy Pharmacovigilance:

Before thalidomide tragedy, the regulatory authorities were working submissively for safety of medicines, much like reactive mode. The steps taken for drug safety or patient safety were merely the reaction to a particular event happened in history and not proactive step for minimising adverse effects before launch of medicine in to market.

In 1848, a 15 year old girl child was died due to chloroform anaesthesia during operating for ingrown toenail; at that time The Lancet a leading scientific research publication house appealed doctors to submit anaesthesia related deaths in Britain^8,7. In 1902, the biological Control Act was enacted in USA for purity and safety of biological like vaccines serums and other such products. The event which was leads to establishment of this act was happened in 1901 in which 13 children were died due to injection of contaminated diphtheria antitoxins^7,9,10.

The following big tragedy which shook the world was happened in 1937; which took 105 lives including 35 children. One pharmaceutical company marketed a well established anti-infective medicine sulphanilamide in new liquid formulation. New elixir form was formulated in raspberry flavour especially for children. Many deaths were reported to American Medical Association (AMA) by doctors due to kidney failures. AMA isolated a toxic substance from this elixir was an ethylene glycol. Then only the physicians were alerted and unused products were recalled. The sulphanilamide event was the major turning point which modified food and drug act into food, drug and cosmetic act (FDCA), enacted in 1938. FDCA was now responsible for regulation of hazardous medical product. FDCA was started government’s attempt to examine risk benefit balance of medicinal product and started asking for safety proof through New Drug Application (NDA)^11,7. The next big amendment in FDCA was done in 1951 which also called the Durham-Humphrey amendment 1951; this amendment categorized drugs into two parts, drugs which required doctor’s prescription and drugs which can take safely without doctor’s prescription. The later were also called over the counter (OTC) drugs¹².

2.2 Thalidomide Tragedy:

Thalidomide was the only non barbiturate sedative available in 1950s. It was synthesized accidently by German Pharmaceutical Company Grunenthal in 1954. After preclinical testing on rats, Grunenthal did brief clinical study on humans for sedation and found it induced sleep in human. Grunenthal marketed the drug over the counter with the tag of completely safe in all. When doctors asked its action on foetus, Grunenthal said ‘unknown’. The first serious adverse effect of thalidomide was reported as peripheral neuropathy in thalidomide long term users. But Grunenthal declined this claim by saying it was rare and reversible if stopped. Meantime, an Australian obstetrician discovered that thalidomide improve morning sickness and started prescribing off label for his pregnant women patients for morning sickness and initiated the trend of prescribing thalidomide to pregnant ladies for morning sickness. In late 1950s and early 1960s, the reports were started appearing across the world from 46 countries where thalidomide was marketed, that, the new born babies were delivered with the serious limb malformation including shortness of both upper and lower limbs and had characteristic feature of Phocomelia. It was observed that these malformations of limbs were seen in the babies of mothers who had taken thalidomide in their second month of pregnancy. Doctors also said that something teratogenic agent had been taken by these mothers during their pregnancy. Though, this serious adverse effect suspecting to be attributed to thalidomide, the Grunenthal declined its association with it, but then they had to stop its distribution from Germany and later it was banned in most of the countries^13,14,15,16.

2.3 Regulations after Thalidomide Tragedy:

How important strict regulations on proof of safety of drugs before its launch in to market was depicted by one incidence happened before this tragedy. When thalidomide was launched in to various countries as a sedative, an US FDA medical officer Dr. Frances Oldham Kelsey declined the proposal of thalidomide to market it in to USA. The basis of this decision of Dr. Kelsey was that thalidomide was never tested in pregnant women and its teratogenic effect was unknown. Dr. Kelsey insisted that, thalidomide drug maker should prove its safety with scientifically sound testing and other complaints before accepting their proposal of marketing. This decision of Dr. Kelsey was later appreciated by American public and government of President John F Kennedy and awarded Dr. Kelsey with President’s Award for her distinguished Federal Civilian Service^17,16. After the tragedy, whole world learned the importance of safety and efficacy testing before its launch in to market. However, different countries made different laws. USA passes amendment in their food, drug and cosmetic act in 1962, commonly known as Kefauver- Harris Amendment 1962. The Kefauver-Harris amendment set up the USAs current skeleton of drug approval through drug discovery, clinical development, testing, marketing and post marketing surveillance throughout the lifecycle of the product by using code of federal regulations 21 which distributed in different parts ^{12, 7}.

Dr. Frances Oldham Kelsey receiving President’s Award for Federal Civilian Service.

Image Courtesy- BBC News Article Anti thalidomide hero Frances Oldham Kelsey dies at 101. Dated 8 Aug 2015

2.4 WHO-International Drug Monitoring:

Soon after thalidomide tragedy, the World Health Organization (WHO) had taken organized international efforts to deal with issue of drug safety. The sixteenth World Health Assembly espoused the resolution, which confirmed the need of rapid action on information of adverse drug reactions. Later in 1968, WHO launched its pilot research project on International Drug Monitoring with purpose to develop internationally applicable system to monitor and detect previously unknown adverse drug reactions. This step of WHO implicated the science and practice of pharmacovigilance and world wide data of ADRs from patient’s file was reported in to central data base of the ADR of WHO through systemic post marketing surveillance via national pharmacovigilance centres of member states. Currently, International Drug Monitoring is coordinated by Uppsala Monitoring Centre, Uppsala, Sweden and more than 136 countries have been participated as member state (WHO) ¹⁸.

2.5 United Kingdom on Pharmacovigilance:

Two years after thalidomide tragedy, UK had formed a committee on safety of drugs (CSD) in 1964; later it was renamed as committee on safety of medicines (CSM). Under this, the government solicited the adverse drug reaction data from the physicians and dentists across UK. For reporting purpose UK developed a yellow card system and these cards were sent to all doctors. This system was popularly known as yellow card system. Pharmacists were involved under this system in 1997, nurses in 2002 and consumers in 2005¹⁹.

2.6 Japan:

In 1967 Japan had established ‘Re-examination System for New Drugs’ under which Ministry of Health and Welfare, Government of Japan seeks novel and serious adverse drug reactions from the hospitals of Japan. The Doctors were supposed to be report all the serious ADRs to the national pharmacovigilance system. Unlike many other systems across world, Japan Government was started rewarding reporting doctors with small amount of cash also^20,7.

3. CURRENT STATUS OF PHARMACOVIGILANCE:

The current status of pharmacovigilance worldwide has been evolved by bearing the brunt of unforeseen events happened in past. After thalidomide tragedy, every country had made laws related to safety and efficacy of medicinal product but there was a need of a common platform worldwide to bring pharmacovigilance process in to uniform procedure right from reporting of adverse drug reaction to the benefit risk analysis and signal detection. There were initiatives taken in past by many organizations including governmental, nongovernmental, non profit organizations to streamline pharmacovigilance system into universally accepted standard procedure and moulded in to current pharmacovigilance system.

3.1 Council for International Organizations of Medical Science (CIOMS):

Council for International Organization of Medical Sciences (CIOMS) was an international nongovernmental, non profit organization established jointly by WHO and UNESCO in 1949. In early 1980s CIOMS has launched its programme on Drug Development and Use with collaboration with WHO, under this programme CIOMS started concentrating their focus on monitoring of drug safety and reporting adverse drug reactions. In 1986, international adverse drug reaction reporting form along with agreed and tested procedure were released for reporting ADRs from pharmaceutical industry to the regulatory authorities of USA, UK, Germany and France. CIOMS working group II delivered the standard format in which periodic summaries have to report to regulators. CIOMS-III working group prepared proposal addressing the preparation of company core data sheet and the standard good clinical safety labelling practices.^21,22.

3.2 International Council for Harmonization (ICH):

ICH was initially consisted of regulatory agencies and industry experts from Europe, Japan and USA. ICH had led down number of guideline on safety, quality and efficacy of new medicinal product²³. After formation of ICH, it was recognised that the use of different adverse drug reaction terminology at different stages was quite difficult, time consuming and costly. This need given rise to the formation of the most advanced adverse drug reaction terminology called Medical dictionary for Drug Regulatory Activities (MedDRA), which has been adopted for regulatory activities related to the ADRs by pharmaceutical companies²⁴. The guideline E2A described standard terminologies for clinical safety reporting and guidance on mechanism for handling rapid reports of ADRs during clinical developmental phases. E2B described electronic transmission of ICSR while E2C described periodic benefit risk evaluation. E2D guidelines described standards and definitions of post marketing expedited reporting. E2E guidelines described pharmacovigilance planning activities for early post marketing period of new drugs mainly focused on pharmacovigilance plan that have to submit during licence application. E2F deals with Development safety update reports^25,26.

3.3 Good Pharmacovigilance Practice:

European Medicine Agency formed in 1995, for ensuring that medicinal products sold in European Union (EU) are safe, effective and high quality. For this purpose EU has set down certain guidelines on safety part of the medicinal product called Good Pharmacovigilance Practice (GVP). The major guidelines on pharmacovigilance process covered in sixteen modules from I to XVI. These guidelines given detailed information of pharmacovigilance system that should be follow by marketing authorization holder of medicinal products, if they want to market their product in any member state of European Union. These new legislation of pharmacovigilance was implemented from July 2012 with release of first seven modules, and then it was expanded to current sixteen modules. Each GVP module is consists of major process under pharmacovigilance activity at MAH level. Two major guidelines according to GVP are that MAH should submit the Periodic Safety Update Report (PSUR) to evaluate benefit risk ration of the marketed drug under module VII and Risk Management Plan (RMP) under module V to EMA. Module VII described that PSUR should submit 6 monthly for first 2 years and then annually for subsequent 2 years and three yearly thereafter, after the date of MAH got permission of marketing the drug in European Union or European Economic Area. More recently this PSUR is replaced by term Periodic Benefit- Risk Evaluation Report (PBRER), (ICH-E2C guideline). All the ADRs in EU region are reported through Eudravigilance^27,28,3.

3.4 USA:

In USA the post marketing adverse drug reaction reporting is done according to Code of Federal Regulation Title 21 part 314, applications for FDA approval to market new drug through section 314.80. FDA submits the reports to FDA Adverse Event Reporting System (FAERS). ADR Form 3500A or 3500B is used for reporting purpose. The prior is used by mandatory reporting from regulated industries while later is used for voluntary reporting from healthcare professional and consumers. Reporting has been done online through med watch. The reported ADRs are assessed by Centre of Drug Evaluation and Research (CDER) or Centre of Biologics Evaluation and Research (CBER). The MAH have to submit periodic report to FDA of risk benefit analysis of their product being marketed in USA, through Periodic Adverse Drug Experience Report (PADER), initially should submit quarterly for 3 years and then after annually²⁹.

3.5 India Initiatives to Strengthen Pharmacovigilance:

Succeeding the history of two attempts to establish pharmacovigilance in India, one in 1986 and another in 2005; India launched its third attempt of establishing pharmacovigilance called Pharmacovigilance Programme of India (PvPI) in July 2010. The skeleton of this system in 2010 consists of 22 ADR monitoring centres mostly placed in government teaching medical colleges, 4 regional centres and one National Coordination Centre (NCC). All India Institutes of Medical Science (AIIMS), New Delhi was acted as NCC on launch of the programme. Later in April 2011 the NCC was shifted to its current location at Indian Pharmacopoeia Commission (IPC), Ghaziabad, UP. In recent time the ADR monitoring reaches 250 centres across India including government and non government medical colleges, corporate hospitals, ICMR research centres and district hospitals. These efforts of Indian lawmakers to reach till district level healthcare professionals for pharmacovigilance ensured that this time pharmacovigilance has been implemented successfully in India. This programme is aimed to collect spontaneous reports of the adverse reactions from healthcare professionals and patients due to medicines marketed in India and the data is being used to assist Central Drug Standard Control Organization (CDSCO) to take decision on safety aspects of marketed medicinal drugs and subsequently forwarded to the Uppsala Monitoring Centre (WHO-UMC). IPC is now a WHO-Collaborative Centre for Pharmacovigilance in Health Programmes and Regulatory Services^30,31,32,33.

More recently, in March 2016, the government of India also amended its schedule Y under Drug and Cosmetic Act 1945. Schedule Y consists of the requirement and guidelines for clinical trials. The new amended version of Schedule Y has given pharmacovigilance guidelines to MAH who wants to market their product in India. According to this guideline the MAH have to establish pharmacovigilance system at MAH level to report all ADRs of their product to PvPI which was not obligatory in past. Schedule Y has also given guidelines on PSUR submission timeline which is same as EMA³⁴. For ADR reporting purpose PvPI has issued suspected Adverse Drug Reaction Form in English for HCPs and in 10 regional languages of India for consumers or non HCPs reporting, both the forms can be downloaded from Indian Pharmacopoeia Commission website or present in any ADR Monitoring Centres across the country.

4. NEW TRENDS IN PHARMACOVIGILANCE:

Over the period of time the pharmacovigilance field has been evolved rapidly through various laws and regulations across world. The stringent laws for safety of drug allow drug makers to see more and more ways to draw maximal data regarding safety of drugs and started using more and more innovative technologies to accelerate the process and reduce pressure to fulfil various requirements of regulatory authorities and more quality oriented work has been started to deliver.

4.1 Social Media:

Internet use is well established in pharmacovigilance fraternity. In USA the adverse effect can directly report to FDA through med watch, in Canada through med effect and in EU through yellow card system. The EU GVP guidelines also focused on internet use for literature search for possible adverse event monitoring in their module VI. Since last 7-8 years social media use like face book and Twitter and more recently Whatsapp has been increased considerably in peoples around the world. So the social media stand out to be the new channel for adverse drug reaction reporting compare to traditional system of PV. Social media serves a more patient centric source of adverse drug reaction reporting, analysing and monitoring safety data. It enables and opens direct communication between healthcare provider and patient. It was observed that online community users tend to share their adverse experience with medicine online to friends and family. One more advantage of this channel of monitoring adverse event is that, this online shared data serves as a documented proof and identity of reporter can be tracked and authentication of adverse experience can be done and it also keep online for longer period of time unless and until it is deleted by reporter himself. It also enables detecting adverse experience due to particular drug by using related words to trace adverse event: medicine combination online^{35,36,37,38,39}.

4.2 Mobile App and Toll free number:

In today’s world mobile phone is doing many tasks on one click through its applications. Many regulators across the world are now using this facility to minimise ADR reporting process to them. In UK the yellow card system was launched many years back to report ADRs but in July 2015 this yellow card system launched their mobile app for ADR reporting. Now the peoples in UK can directly report ADRs to regulatory authority through this Yellow Card Mobile App³⁴. Indian Pharmacopoeia Commission also launched its mobile app in May 2015 to facilitate ADR report to Pharmacovigilance Programme of India. Along with mobile app PvPI has also launched a toll free number 1800-180-3024 for direct ADR reporting to regulatory authority. A toll free number is managed directly by staff of PvPI at National Coordination Centre and the details of the ADRs then forwarded to nearest ADR monitoring Centre of that region. By this way if the ADR was reported by non healthcare professional then medical confirmation is done by HCPs at ADR monitoring centre by visiting the reporter⁴⁰.

4.2.1 WEB RADR:

WEB RADR is the app developing services that developed mobile app for the adverse drug reaction reporting which had developed yellow card mobile app for UK, LAREB app for reporting in Netherland, HALMED app for reporting in Croatia. WEB RADR had also created app for some African countries including Burkina Faso and Zambia^41,42.

4.3 Outsourcing:

Outsourcing is providing the solution to pharmacovigilance industry to carry out complex PV procedures from specialized pharmacovigilance team at contractor workplace without hiring these professionals on their own. These outsourcing companies offer end to end pharmacovigilance services including case processing, medical affairs, regulatory affairs and risk management services. It is on pharmaceutical companies that, what they want to outsource. Some pharmaceutical companies outsource some part of the pharmacovigilance process (ICSR processing) and doing later part in their own company while some pharmaceutical companies outsourced entire process of pharmacovigilance. These outsourcing companies mainly are the individual consultant, speciality contract research organization, full service CROs or Knowledge process outsourcing (KPO) firms. These companies have a robust technology and specialist teams to carry out complex PV tasks^43,44,45,46.

4.4 AUTOMATION: Artificial Intelligence, Machine Learning and Natural Language Processing:

Much talked topic since couple o years in pharmacovigilance is Artificial Intelligence (AI), machine learning, and natural language processing, in short cognitive computing. Regulations under good pharmacovigilance practice stipulate that drug maker should go further and become proactive for patient safety. In pharmacovigilance, for safety signals, drug makers are depends on their web sites, forums, incoming mails and calls and scientific literatures. But in reality signal could be appeared in twitter post, face book post, independent patient forums and blogs, comments published in WordPress and also via YouTube and pintrest sites. It was believed that 10-17% of the ADRs missed due to drug makers are not able to detect ADRs from these channels. To deal with this ocean of possibilities AI was started appearing in news. AI is now started beginning to transform what human teams can do. Natural language processing and AI can now filter and clean data by reducing irrelevant and false data. It has ability to interpret human languages, analyse short message on twitter to the long paragraphs in WordPress. This is now considered to be the real game changer in pharmacovigilance, decreasing the cost of case processing and improving data quality. In presence of such advantageous factors of AI, there are some doubts about its trust. Drug makers like the idea of AI, but they are concerned that automation won’t produce the same outcome as manual case processing. So it is now the wait and watch period for all pharmacovigilance fraternity to see effect of AI on pharmacovigilance^{47,48,49,50,44,51,52,}

4.6 Vaccine Pharmacovigilance:

The world of the vaccine is changing rapidly and so its safety concerns. In view of resource limited setting for safety of vaccine, the pharmacovigilance of vaccine will became necessary. On the dawn of decade of vaccines launched by WHO in 2010, the vaccine safety strategy, Global Vaccine Safety Blueprint was given by world health assembly in The Global Vaccine Action Plan. This blueprint will ensure that every country in the world should have at least minimal capacity for vaccine safety. This document contains the strategic plan for strengthening vaccine safety activity globally. To implement this strategy, the Global Vaccine Safety Initiative (GVSI) was set up. This GVSI comprises eight objective aimed to focus on building and supporting systemic approach to vaccine pharmacovigilance in all LMIC. These eight objectives are 1) Adverse event following immunization (AEFI) detection 2) Investigation of safety signals 3) Vaccine safety communication 4) Tools and methods 5) Regulatory framework 6) Technical support and training 7) Global analysis and response and 8) Public private information exchange^53,54,55.

4.7 Active Pharmacovigilance: Sentinel Initiative:

As we discussed earlier that after thalidomide tragedy the global pharmacovigilance was shifted to proactive mode from reactive mode. But the FDA thought in 2008 that this efforts of seeking safety data from spontaneous reporting and clinical trial reporting were not sufficient to take action on drugs marketed in USA. So USA launched its project Sentinel Initiative in 2007 and the pilot version of this project Mini Sentinel Initiative. Under this project FDA seeking safety data more actively called ‘Active Pharmacovigilance’ than Passive Pharmacovigilance through national electronic system for monitoring the safety of FDA approved medicine. This Sentinel System will augment with current post marketing surveillance system and not replace it. This combination of passive and active surveillance give 360 degree view of safety issues related to the medicinal products approved by FDA. This trend of active pharmacovigilance will beneficial not only to FDA but to entire pharmacovigilance drug regulators globally^{56,51, 37}.

4.8 Pharmacogenomics-Personalised Medicine:

As discussed earlier the new drug is exposed to very limited number of people in very strict conditions in clinical trials, so possibility of identifying population with either increased or decreased response to medication due to genomic variations are difficult during clinical development. Identification of such population with specific genotype and phenotype will benefit for tailoring the therapy to such population for minimising the risk and increasing the efficacy of the medicine. From the other side, along with favourable clinical outcome it will also have economic benefit to patient as more correct medicine will be given instead of trying irrelevant medications on patient. Committee for Medicinal Products for Human Use (CHMP) of European Medicine Agency led down some guidelines for key aspects for the use of Pharmacogenomics in pharmacovigilance. This Pharmacogenomics trend will impact positively on pharmacovigilance, as a less number of adverse events will be generate but demand of more quality data will increase^{57,58,59,35,37}.

4.10 Non Interventional Studies/ Observational Studies:

The interest in non interventional studies in pharmacovigilance has been increased since last few years. Non interventional studies after marketing of drugs have their origin in to the GVP module VIII, post authorization safety study. As a name indicated this study has no intervention in patient’s treatment. Under this study researcher only observe the patient treatment in clinical setting and noted down various events happened during treatment. It not involved treatment suggestion or modification. NIS was implicated to observe safety and efficacy of the drug after marketing. NIS may involve questionnaire, interviews or study specific blood sampling. This data provide evidence to MAH or regulators in decision making process about safety of drugs^60,61.

5. CONCLUSION:

Global pharmacovigilance has come far afield since its inception after thalidomide tragedy in respect to quality, speed and invention of novel methods and technologies. Though pharmacovigilance was started many years before and that was evidenced from some discrete events happened in past, thalidomide tragedy was the real milestone in the history of pharmacovigilance. Stringent regulations on safety of drugs brought pharmacovigilance in spotlight and pharmaceutical industry went round a clock to fulfil the entire safety data requirement to avoid rejection of their products. In this journey many governmental, nongovernmental organizations came up with their guidelines and regulations to rationalize pharmacovigilance process on global platform. Pharmaceutical companies were started using innovative methods and novel technologies for adverse drug reaction detection and monitoring to keep watch on their products performance in real time world and speed up the regulatory processes. This new trends are carrying forward the global pharmacovigilance and made the process more and more precise.

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Received on 08.05.2023 Modified on 13.12.2023

Asian J. Pharm. Res. 2024; 14(2):175-182.

DOI: 10.52711/2231-5691.2024.00029