Nepal’s Pharmacovigilance Initiative: Progress and Challenges

Words by Suman Shahukhal

Clopidogrel is a widely prescribed antiplatelet drug and if you practice internal medicine or cardiovascular medicine, you certainly may have prescribed the drug to multiple patients, right? There has been a revision in the guidelines for Clopidogrel use based on Pharmacovigilance data. The pharmacovigilance studies revealed that individuals with certain genetic variations in the CYP2C19 enzyme had reduced activation of Clopidogrel, a widely prescribed antiplatelet prodrug. This decreased efficacy increased the risk of cardiovascular events in these subsets of patients. As a result, pharmacovigilance-led findings prompted revised guidelines recommending alternative medications or personalized dosing for individuals with these genetic variations. This is just an example to instill the idea on the importance of carrying out pharmacovigilance studies. 

Pharmacovigilance programs stand as robust pillars within healthcare systems worldwide, serving to bolster patient safety. The drug reactions within a diverse population emphasizes the pressing need for proper surveillance in different countries and hospitals. Variations in genetic predispositions among populations can significantly alter drug responses, often resulting in disparate side effects that might go undetected without comprehensive pharmacovigilance initiatives. Moreover, the reliance on data primarily drawn from clinical trials, often conducted in select demographics or regions, underscores the necessity for continuous monitoring and reporting within local contexts. Even with adult dosage recommendations, largely based on data extrapolated from trial subjects in distant geographical locations, the relevance and impact of such doses within various subsets of the global population remain uncertain. Therefore, the meticulous documentation and analysis of adverse drug reactions is of paramount importance, shedding light on various adverse drug reactions and aiding in the promulgation of medication protocols tailored to specific populations.

Drugs (Medicines and vaccines) have transformed the prevention, diagnosis and treatment of diseases. In addition to their benefits, drugs may also have side effects, some of which may be undesirable/unexpected and harmful. Such undesirable/ unexpected and harmful effects of drugs are adverse drug reactions (ADRs).

All drugs undergo rigorous testing for safety and efficacy through clinical trials before they are authorized for use. However, the clinical trial process involves studying these products in a relatively small number of selected individuals for a short period of time. Certain side effects may only emerge once these products have been used by a heterogeneous population, including people with other concurrent diseases, and people on multiple medications over a long period of time. Reporting of ADRs helps prevent reoccurrence and presents robust data for determining the safety of drugs even in comorbid conditions.

The World Health Organization (WHO) defines Pharmacovigilance (PV) as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine/vaccine-related problems”. 

History of PV started in the 1960s with the thalidomide tragedy. Thalidomide was approved and marketed as an effective hypnotic drug and also for morning sickness/nausea in pregnant women. But later that year, more than 20000 cases of deformed infants were reported. Women, who were under thalidomide, delivered babies with deformed limbs(phocomelia). As a result of this tragedy, the drug was banned for use. In 1962, US-FDA amended a compulsory requirement for safety and efficacy data for every drug for registration in federal food, drug and cosmetic act. In 1963, during the 16th World Health Assembly, resolution 16.36 called for “a systematic collection of information on serious adverse drug reactions during the development and particularly after medicines have been made available for public use”. This led to the formation of the WHO Programme for International Drug Monitoring (PIDM) in 1968 and the establishment of the Uppsala Monitoring Centre(UMC) in Sweden. In 1964, UK amended a yellow card scheme for reporting of any suspected ADRs by including an yellow card for ADR monitoring in the British National Formulary (BNF) which they provided free of charge to all the healthcare professionals working under the NHS scheme.

WHO-UMC, Sweden is an international PV center and receives the reports from national PV centers while national PV centers receive reporting from regional PV centers. PV consists of two processes: Mandatory reporting and Spontaneous reporting. Drug manufacturers need to submit the ADR report received from Health Care Professionals (HCPs) to national authority periodically (quarterly, bi-annual or annual) in the form of Periodic safety update report (PSUR). Internationally this reporting is mandatory for renewal of marketing license of the product/drug but currently this process is not mandatory in Nepal. Spontaneous reporting is the most common form of ADR reporting. Consumers/Patients, HCPs can submit any suspected ADRs to regional PV centers or directly to national PV centers by filling the reporting form. Regional PV centers report the ADRs to national PV centers via Vigiflow database and National PV centers forward the reports to UMC via Vigilize database. The ADR report is called Individual Case Safety Report (ICSR) and this reporting process is voluntary. For this spontaneous reporting, the three must have details for ADR reporting are:

1. i) drugs (Generic name, brand name), 
2. ii) patient’s details (age,sex, comorbidity) and 

iii) the nature of reaction(details of reaction, time of onset). 

WHO-UMC data update as of July 2023 shows that there are over 35 million reports of adverse reactions in VigiBase. Data in VigiBase are recorded in a structured and comprehensive way to allow the detection of potential medicinal safety hazards.

The Government of Nepal nominated the Department of Drug Administration (DDA) in October 2004 as the focal point (National Pharmacovigilance center) to liaison with WHO collaborating center for International Drug Monitoring, UMC-Sweden and started collecting adverse drug reactions. Nepal became a WHO-UMC programme member in July 2006. There are currently 15 regional PV centers in Nepal. The regional PV centers are: 

1. Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu 
2. Civil Service Hospital, Minbhawan, Kathmandu
3. Manipal Teaching Hospital, Pokhara 
4. Dhulikhel Hospital, Dhulikhel
5. KIST Medical College, Lalitpur
6. Nepal Medical College Teaching Hospital, Jorpati, Kathmandu
7. Patan Hospital, Lalitpur
8. B.P Koirala Institute of Health Science (BPKIHS), Dharan
9. Shree Birendra Hospital, Chhauni
10. Norvic International Hospital, Thapathali
11. Nepal Cancer Hospital and Research Center, Harisiddhi, Lalitpur
12. College of Medical Sciences – Teaching Hospital, Bharatpur, Chitwan
13. Nepal Mediciti, Kathmandu
14. Chitwan Medical College, Chitwan
15. National Tuberculosis Control Center, Bhaktapur

These regional pharmacovigilance centers operate under DDA. The regional centers report ADRs to the National center (DDA) via ‘Vigiflow’ (an online program) which are then forwarded to the Uppsala Monitoring Center (UMC) by the National Centre. Till the end of 2022, the National database of Nepal contains about 972 ADR reports so far.

Dhulikhel Hospital became the regional pharmacovigilance (PV) center on July 5, 2017. Since then, the Pharmacovigilance and Drug Counseling Unit has been reporting the ADRs from the hospital and surrounding areas. The reporting is done via its own ADR reporting form. The unit has been actively collecting and reporting adverse drug reactions (ADRs) to the national PV center and thus to UMC via Vigiflow since Jan 2023. For this, it also provides continuous service education for the dissemination of ideas regarding PV and ADR reporting to healthcare professionals in the hospital quarterly. Currently this unit has 2 clinical pharmacists for PV and a pharmacist for drug counseling.

Through ward rounds, patients who are at risk of developing any ADRs and are prescribed with drugs most likely to cause ADRs are monitored. Any incidence of ADRs in the hospital are collected through these ward rounds and by communication with healthcare professionals (Clinicians, Nurses). The ADRs and MEs from OPD are noted from the drug counseling unit. Additionally, this unit also serves to provide any drug-related information to patients and health care providers. The PV unit also issues drug allergy cards to patients who encountered allergic drug reactions to prevent reoccurrence.  More than 130 ADRs have been reported since January 2023 from the unit. 

Every year WHO-UMC considers (6th-12th) November as Med Safety Week to aware the public and healthcare professionals on safety use of medicines and encourage reporting of any ADRs encountered. WHO-UMC organizes #MedSafetyWeek, an international social media campaign, to raise awareness of ADRs and national ADR reporting systems. It aims to educate the public on how patients, doctors, pharmacists, and other healthcare professionals can contribute to pharmacovigilance and achieve the following objectives: encourage people to look out for and report side effects; educate on how everyone can help report side effects of medicines; increase awareness of pharmacovigilance and national reporting systems.

 

Pharmacovigilance in Nepal faces certain challenges, the major one being underreporting. There is still very little awareness among the public about the reporting of any unexpected/undesirable and harmful effects of drugs. One can report these ADRs from the nearest regional PV center or to their healthcare professionals. Other challenges are: prevention of the incidence of ADR because some unpredictable ADRs, commonly known as hypersensitivity reactions, are not seen unless a drug is administered or a patient has a previous history. This history or prior reporting helps in issuance of drug allergy cards thus helping in prevention of recurrence. Communication with stakeholders (DDA, Ministry of Health, and Population of Nepal) for a more effective PV program nationwide is another challenge. Public awareness program plays a pivotal role in the ADR reporting system. Awareness on the concept, rationale and importance of ADR reporting is of the paramount importance for the solution. Drug counseling sessions also play a vital role in ADR reporting. Patients should be counseled about proper drug/ medicine use for optimum therapeutic effect and they should report any suspected ADRs experienced during the therapy. The aims of PV are to enhance patient care and patient safety in relation to the use of medicinal products and to support public health programs by providing reliable, balanced information to assess the risk-benefit profile of medicines.

 

References:

1. https://www.who.int/teams/regulation-prequalification/regulation-and-safety/pharmacovigilance
2. https://who-umc.org/about-the-who-programme-for-international-drug-monitoring/# 
3. https://www.dda.gov.np/content/pharmacovigilance 
4. Gupta, S.K.;Srivastava,S.(2023).Textbook of Pharmacovigilance: Ensuring The Safe Use of Medicine. Jaypee Brothers, New Delhi.