Vaccine pharmacovigilance in India: Current context and future perspective.

Pharmacovigilance of vaccines is of paramount importance to promote the safe use of vaccines among their recipients. India launched the Adverse Events Following Immunization (AEFI) surveillance program in 1986 for monitoring suspected adverse events following immunization and since then, the AEFI surveillance guideline has been updated periodically, with the latest being in 2015. The successful AEFI surveillance program in India required the concerted effort of all stakeholders such as National AEFI Secretariat, National Technical Collaborating Centre, Central Drug Standard Control Organization, marketing authorization holder, and health-care professionals. Copyright:

Introduction

The unfortunate thalidomide tragedy compelled the regulatory agencies across the world to make the drug approval process more stringent. Subsequently, the concept of pharmacovigilance and drug safety was initiated to monitor/investigate adverse events (AEs) following the use of drugs/vaccines.[1]

Vaccines account for a meager percentage of the pharmaceutical products; however, they play a pivotal role in modern health-care delivery. Over the years, vaccination has prevented many serious illnesses and disabilities and saved millions of lives across the world.[2] The diseases which once wreaked havoc on humankind by inflicting severe damage in terms of mortality and morbidly are now either eradicated or quelled due to the extensive use of vaccines.[3] The World Health Organization (WHO) has defined vaccine as a biological preparation which functions by inducing the immune system of the body to elicit an immune response to a particular pathogen.[4] Vaccines are usually regarded as innocuous, but like any other drug products, they are not absolutely harmless, and sometimes AEs might occur following their administration [Table 1].[567]

Table 1

Rare adverse events associated with vaccines and their onset interval

Vaccines	Adverse events	Onset interval
Rota virus	Intussusception	3-14 days
OPV	Vaccine-associated paralysis (AFP)	4-30 days
Tetanus	Brachial neuritis	2-28 days
BCG	Disseminated BCG infection	1-12 months
Hepatitis B	Anaphylaxis	0-1 h
Measles	Encephalopathy	6-12 days
DTP	HHE	0-48 h

Source: Immunization Handbook for Medical Officers (https://mohfw.gov.in/sites/default/files/unit6adverseeventsfollowingimmunization.pdf). OPV=Oral polio vaccine, AFP=Acute flaccid paralysis, BCG=Bacillus Calmette-Guérin, DTP=Diphtheria-tetanus-pertussis, HHE=Hypotonic hyporesponsive episode

It has been observed that even minor incidences of adverse events following immunization (AEFI) have wider social and political ramifications.[8] The public trust withers and vaccination campaign suffers jolt when reports of AEs following vaccination make headline in media. This is so because, unlike other drug products, vaccines are given to the healthy people, mostly to the vulnerable population like children, and the discernible benefit of the vaccine is remote, whereas an associated AE is noticed immediately.[9]

The WHO/Council for International Organizations of Medical Sciences (CIOMS) working group has defined “adverse event following immunization (AEFI) as any untoward medical occurrence which follows the immunization and which does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavourable or unintended sign, an abnormal laboratory result, symptom or disease.”[10] According to the CIOMS, AEFI could be a vaccine product-related reaction, a vaccine quality defect-related reaction, an immunization error-related reaction, an immunization anxiety-related reaction, or a coincidental event.[10]

Vaccine pharmacovigilance is defined as “the science and activities relating to the detection, assessment, understanding, prevention, and communication of AEFI or of any other vaccine or immunization-related issues.”[10] The primary intention behind initiating a vaccine pharmacovigilance program (part of which is the AEFI surveillance program) was to ensure the safety of people receiving the immunization.

Global Scenario

Many countries carry out monitoring of AEFI by an effective national AEFI surveillance system.

The Vaccine Adverse Event Reporting System is a national program to monitor the safety of US-licensed vaccines. This program was commenced in 1990 and co-sponsored by the United States Food and Drug Agency and the Centers for Disease Control and Prevention. This is a spontaneous reporting system where anyone (vaccine manufacturers, health-care providers, vaccine recipients, and parents) can report any clinically significant AEs which occur following vaccination.[1112]

The Canadian Adverse Events Following Immunization Surveillance System is the postmarketing safety monitoring system of marketed vaccines in Canada.[13] It was established by the collaborative effort of federal, provincial, and public health authorities of Canada and managed by the vaccine safety section of the public health agency. It follows both passive and active surveillance to gather data on AEFI from different collaborators such as provincial and territorial health departments, health-care professionals, and pharmaceutical industries.[14]

In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) is at the helm of monitoring the safety of all marketed medicines including vaccines. The suspected AEs following the use of vaccines can be reported to the MHRA through the Yellow Card Scheme.[15]

Indian Perspective

India is one of the largest manufacturers and exporters of vaccines in the world. Apart from that, India runs one of the largest immunization programs (Universal Immunisation Program [UIP]) in the world for the prevention of various vaccine-preventable diseases targeting approximately 27 million newborns and 30 million pregnant women every year.[1617] The detection of all possible AEs during the various phases of the clinical trial is near impossible; hence, postmarketing surveillance (PMS) plays a major role in evaluating the safety of the vaccine. AEFI surveillance program was initiated by the Government of India way back in 1986 shortly after the launching of UIP in 1985.[18] The primary purpose of starting this program was detection of AEFI, swift management, and appropriate action to prevent such events in future. However, for a considerable period of time, the AEFI was not satisfactory.[18] Taking that into account, the Government of India published the first operational guideline for AEFI in 2005 with the technical support of WHO and disseminated it among the medical officers across the country to strengthen and systematize the AE reporting system. This guideline was revised and updated in 2010. In the meantime, national and state AEFI committees were set up in 2008 to strengthen the reporting of AEFI which were further reorganized in 2013 to bring extensive expertise and wider perspective.[19] In the same year, the National AEFI Secretariat and National AEFI Technical Collaborating Centre were established at the Immunization Technical Support Unit of Health and Family Welfare Department and Lady Hardinge Medical College (LHMC), New Delhi, respectively, for technical oversight and support [Figure 1]. Pursuing the agenda of effective implementation and surveillance on vaccine safety, the Government of India brought out another revised AEFI guideline which was prepared in accordance with the WHO/CIOMS guideline in 2015.[2021]

Figure 1

Source :National quality assurance standards for AEFI surveillance program

Documenting and Reporting Adverse Events Due to Immunization

The 2015 guideline has broadly classified AEFIs into three categories: (1) common minor AEFIs – they include local reactions, fever, and systemic symptoms; (2) serious AEFIs – those AEFIs which result in hospitalization, death, or significant disability; and (3) severe AEFIs – reactions which are not minor but do not also result in disability or death and do not require hospitalization. India, like many other countries, follows the passive reporting procedure. The revised guideline emphasizes to report all types of AEFIs. All severe AEFIs are to be reported immediately in a case reporting format by the medical officer in charge or any other reporter, and the report should be sent to the district immunization officer (DIO) within 24 h. The job of the DIO is to verify the report diligently and dispatch it to the state and national level committees in the next 24 h. The other means of reporting AEFI is through a monthly progress report in which all AEFIs (severe and minor reactions) shall be reported in monthly reporting format like health management system. It is also imperative for the peripheral health worker to submit a nil report if no reaction is reported during the entire month. The guideline also emphasizes on making the private players aware of the existing AEFI reporting mechanism and motivate them to report the same.[162122]

Documenting and reporting AEFI is teamwork, and seamless flow of information involves the role of different stakeholders, as follows [Figure 1]:

Peripheral health workers

Peripheral medical officers

Private practitioners

DIOs

State immunization officer

Role of AEFI secretariat

Role of national AEFI committee

Role of marketing authorization holder (MAH).

Causality Assessment of Adverse Events Due to Vaccines

Causality assessment is defined as the systematic measurement of the strength of association between the exposure and occurrence of an event. There are many established algorithms to perform the causality assessment for the suspected adverse drug reaction (ADR), namely WHO-Uppsala Monitoring Centre and Naranjo ADR probability scale. Similarly, for the AEs associated with vaccines, causality assessment is essential. The 2015 revised guideline has adopted the CIOMS/WHO 2013 revised casualty assessment which states that causality assessment should be done at the population as well as the individual level and for signal detection. Causality assessment process involves four steps, namely eligibility, checklist, algorithm, and classification.[21] Causality assessment is done by the experts of AEFI at national level. The regular causality assessment meetings are conducted by the Secretariat in the National AEFI Technical Collaborating Centre setup at Lady Hardinge Medical College(LHMC). Deaths attributed to AEFI are rigorously reviewed again by an expert panel comprising chairs of four subcommittees of the national AEFI committee (causality assessment, investigation, media, and laboratory subcommittees) and chairman of the national AEFI committee. Results of causality assessment are periodically uploaded on the Ministry of Health and Family Welfare (MoHFW) website for public viewing.[2223]

Role of National Coordinating Centre-Pharmacovigilance Program of India in Vaccine Pharmacovigilance

The Government of India initiated the Pharmacovigilance Program of India (PvPI) under the aegis of the Central Drug Standard Control Organisation (CDSCO) for monitoring AEs due to drugs.[24] Since its launch in 2010, the PvPI has expanded by setting up ADR monitoring centers (AMCs) in different parts of India and playing a vital role in reporting suspected adverse drug reactions from across the country.[17] PvPI also has an equally important role in vaccine pharmacovigilance. National coordinating center collates all AEFI data received from various AMCs and shares it with the respective DIO, state AEFI committee, and national AEFI committee for examination and recommendation. The pharmacovigilance division of human vaccine within the biological division of CDSCO headquarter is responsible for the collection and compilation of PMS and periodic safety update report data from the MAH. Results of the various causality assessments approved by the National AEFI Committee are shared with the CDSCO, which in turn looks for any kind of signals generated from these reports. A signal review panel is established at the Indian Pharmacopeia Commission (IPC) which discusses different cases and shares it with the AEFI secretariat and CDSCO.[25] If a signal is detected, the MoHFW will inform the CDSCO to take necessary regulatory actions (inspections, amendments to product inserts, etc.).

The Road Ahead

The AEFI surveillance system in India has strengthened since its initiation; however, it is still saddled with many challenges. Although the AEFI committee is constituted in all districts of the country, the major challenge is adequate and timely reporting of AEFI in a correct manner. Health-care professionals such as peripheral health workers (Anganwadi workers, accredited social health activists, auxiliary nurse midwives, and health supervisors) and medical officers at primary health care and community health care level have an important role in reporting suspected AEFI. Although requisite periodical training has been prescribed for them in the guideline, there is not much research data available in public domain pertaining to health-care professional's knowledge, skill, attitude, and practice toward reporting of AEFI. Periodic training in the form of continuing medical education, workshops, and hands-on training for staff (field health workers, immunization officers, and medical officers) associated with immunization should be provided to enhance their skill for correct reporting. Officials associated with the vaccine pharmacovigilance program at district, state, and national level should be encouraged and empowered for effective implementation of the program. Private practitioners are important partners in the vaccination program. Data suggest that 10%–20% of the routine immunization in India is provided by them, and the numbers are even higher for the vaccines which are not included in the UIP. However, reporting of AEs associated with vaccination from them is not encouraging.[20] An initiative like web-based reporting system developed by the Indian Academy of Pediatrics has not been very successful as private practitioners are not much aware of their role in vaccine pharmacovigilance.[20] The success of the vaccine pharmacovigilance program depends on greater cooperation and collaboration, innovative solution, and exploitation of modern technology greater good. Measures such as regular sensitization of private physicians about AEFI; dissemination of information about AEFIs; and stronger collaboration of PvPI and AEFI surveillance program with professional bodies such as Indian Medical Association (IMA) and Indian Academy of Paediatrics(IAP) are essential to make the pharmacovigilance program of vaccines more effective and robust.

Eminent American psychologist Rollo May famously said: “Communication leads to community, that is, to understanding, intimacy, and mutual valuing.” The MoHFW has recognized the immense role of effective communication in dispelling doubt and distrust toward immunization by shattering the myths and misconceptions around AEFI. It has launched a special program in 2013 to enhance the communicative skill of health-care providers, for building vaccine confidence around AEFI.[26] India is witnessing a phenomenal rise in the number of smartphone users and is expected to reach approximately 500 million in 2022. With such deep penetration of mobile phone, it is expected that social media will have a staggering role in communication by disseminating information as well as misinformation. It is evident in different studies that proper application of social media has a positive influence on vaccine behavior.[2027] Hence, AEFI surveillance program in India also needs to adapt to today's technology to propagate positive news and proper information regarding the virtue of immunization among the general public.

Conclusion

In a modern developed democracy, no child should suffer from a vaccine-preventable disease. The immunization coverage in India is gradually increasing, and new vaccines are being added up in the national immunization program. However, sometimes, people are reluctant to take part in immunization campaigns because of many factors, and the fear of AEFI is one among those. The information gap regarding the safety of vaccination and AEFI has always been a cause of concern among the vaccine receivers; hence, it is important for the health-care agencies to take necessary steps to allay the apprehension of people toward vaccine safety. Effective communication is necessary to convince the people that benefits by outweighing the risk by many folds in the case of vaccines. It is also essential to convince people that though AEFI sometimes is inevitable, most of the times, it does not carry any significant risk. AEFI surveillance is a crucial program initiated long back to prevent the AEFI and to ensure safety. There is a need to improve the awareness about reporting among the medical professionals working in public as well as the private sectors to report all suspected AEs associated with immunization so that proper steps can be taken to prevent such incidents in future. The vibrant AEFI program will go a long way in winning the faith of people toward immunization.

Financial support and sponsorship

This is a self-funded study.

Conflict of interest

There are no conflicts of interest.