By Debaleena Basu
A healthy 21-year-old youth was admitted to a hospital for an elective surgery. All preoperative physiological parameters were normal. On the surgery day, the commonly used drug bupivacaine was administered to induce spinal anaesthesia. Following the injection, he immediately went into shock. His blood pressure dropped, pulse weakened, and his breathing became abnormally rapid. Efforts made to reverse the situation failed and he succumbed within a day.
This case report is one of the five mentioned in a May 2014 study published in the Indian Journal of Critical Care Medicine, which documented casualties arising from adverse reactions to drugs (ADRs) in an Indian hospital. Adverse drug reactions refer to undesirable effects of a drug beyond its expected therapeutic function and often have serious consequences.
Drug toxicity has become a major concern for healthcare providers globally and is reported to be among the top ten causes of death. It poses an economic as well as public health burden on nations. With more and more new medicines being introduced in the market, active monitoring of the side effects of drugs has become the need of the hour.
One may ask why there are any adverse effects at all! Aren’t all licensed medicines safe? In the above case, a commonly used anesthetic, bupivacaine was administered. Discovered in 1957, the chemical bupivacaine has undergone multiple clinical trials to estimate its safety and efficacy. Today, it is a frequently used drug, and is also a part of the World Health Organisation (WHO) model list of essential medicines, a compilation of necessary medicines required for a basic healthcare system. Yet, the usage of such a tried-and-tested, frequently applied drug, took a tragic turn, resulting in an unexpected and untimely death. ADRs are on the rise due to various factors, a major one being the inherent shortcomings of the drug discovery and approval process.
New promising chemical compounds discovered in the lab go through a rigorous drug development process to establish the basic properties such as the chemical makeup, toxicity and stability of the compounds. Pre-clinical tests, also known as animal trials, involve testing on animals, and the information gathered helps in deciding the start of clinical trials on humans.Clinical trials with human volunteers are conducted in phases, with each approved phase progressively testing the safety and efficacy of the experimental drug in larger cohorts of people. However, even at the end of all the three phases of the trial (Phase-I, II & III), the effect of a potential drug is studied only in a select group of typically 5,000 volunteers or less.
That a drug, which is 100 per cent selective and specific in its therapeutic action and has no adverse side effects in the body, is at best a mythical one. The clinical trial mechanism is there to only allow potential drugs that maximize benefit to be released into the market. Even with the current improved standards of clinical trials, every possible side effect of the drug may not show up during evaluation.
For one, rare adverse effects may not get manifested in the limited patient pool tested in clinical trials. Additionally, clinical trials only report adverse reactions that appear within the limited duration of the trial. Also, children, pregnant women, and the elderly are typically not included, or under-represented in clinical trials, and thus, the safety of the drug in these cases remains unknown until its release.
The only way to find out about such adverse reactions for drugs being currently used by the public is by being vigilant for negative side effects, and accordingly, regulating the drug’s description and distribution.
Monitoring adverse drug reactions
India is a developing country having a large drug consuming population with substantial ethnic variability. It is the third largest producer of pharmaceuticals by volume in the world and new medicines are continually flooding the market. It is crucial that adverse drug reactions are identified as early as possible to ensure the well being of the populace at a reasonable cost.
The WHO established its Program for International Drug Monitoring in response to the thalidomide disaster. The WHO international collaborating center at Uppsala promotes drug monitoring at the country level.
Following a number of unsuccessful attempts, the current nation-wide Pharmacovigilance program of India (PvPI) was initiated in 2010 in collaboration with the WHO’s drug monitoring program.
Pharmacovigilance refers to the detection, assessment and prevention of adverse drug reactions. The program is overseen by the Central Drugs Standard Control Organization (CDSCO), under the aegis of the Ministry of Health and Family Welfare.
Healthcare professionals have most important role to play in pharmacovigila nce. William McBride, an Australian doctor, published the now famous case report in The Lancet in 1961, suspecting a causal link between thalidomide intake and serious foetal deformities, which ultimately lead to the banning of the drug. He is considered by many to be the first ‘pharmaco-vigilante’.
The physician is the one who has knowledge of the patient’s medical history, and is the first one to suspect an ADR, thus it is crucial for any pharmacovigilance program to recruit as many doctors as possible. Under the PvPI, 179 hospitals and medical institutes, both government and private, have doubled up as ADR monitoring centers.
When an ADR is suspected, any medical personnel (doctors, nursing staff, interns) can report it. Patients experiencing side effects can also submit reports about the drug. Reports from the individual monitoring centers are collected and analyzed at the national coordinating center for PvPI, the Indian Pharmacopoeia Commission (IPC) at Ghaziabad. If the ADR data is found to be robust and ‘valid’ after review, the IPC recommends regulatory interventions to the central drug regulatory authority. It also communicates the risks associated to healthcare professionals and the public through quarterly newsletters. Additionally, the IPC contributes the reports to the global ADR database (Vigibase) maintained at WHO’s Uppsala Monitoring Center.
Pharmacovigilance in action
Many of us do not look through the package inserts of medicines, containing the list of possible side effects in miniature font. Each side effect is included only after careful evaluation of test results by expert committees. The interest of the pharmaceutical companies lies in keeping the list small, while that of patients’ is in knowing about all possible reactions.
The drug carbamazepine is a commonly prescribed anticonvulsant medicine for epilepsy, and falls under the WHO’s recommended essential medicine list. The PvPI received 1887 reports (over a period of three years) of adverse drug reactions associated with carbamazepine from the nationwide ADR monitoring centers, out of which 119 were life threatening or fatal. Furthermore, a certain genetic variant commonly found in the Indian population (HLA-B* 1502), was found to be strongly associated with severe ADRs.
Based on the reports submitted by doctors to the PvPI database, the IPC recommended a label change to include the risk factors. The central drug regulatory body (CDSCO) has recently issued a directive for all manufacturers to revise package inserts of carbamazepine after reviewing the recommendations, in a bid to sensitize healthcare providers to the observed risks.
The road ahead for PvPI
India’s current pharmacovigilance program has made notable progress in the past few years. According to a PvPI update, India is the first Asian country to have more than 1.0 lakh individual case safety reports in the Uppsala center’s global database, making it among the top 10 countries to have submitted reports in 2015. However India’s contribution at 2 per cent was far behind that of two other Asian countries, China (8 per cent) and Korea (11 per cent).
The national PvPI coordination center, IPC, is set to become the first WHO Collaborating Centre for Safety of Medicines and Vaccines in the South-East Asia region. The Uppsala center gives a completeness score to every national program, indicating the how adequate the reports submitted are. India has got an impressive 0.94 out of 1, placing PvPI among the top-rankers and pointing towards the high quality of adverse effect reports submitted to the WHO.
Sten Olsson, program expert at the Uppsala monitoring center, has lauded India’s fledging pharmacovigilance program, stating: “Although India has a long way to go in the area of pharmacovigilance, it has created a momentum in ADR monitoring. The World Health Organization’s Uppsala monitoring center is now looking to make India a hub for pharmacovigilance training”.
However, for a country of 1.252 billion, the current scale of PvPI is alarmingly small. Drug monitoring needs to grow at an accelerated pace to quickly ensure patient safety. Adverse drug effects are grossly underreported, mainly due to the limitations of resources and lack of awareness among healthcare professionals.
The PvPI has steered continuing medical education programs that aim to promote ADR reporting and greater participation in pharmacovigilance. To encourage the ADR reporting process, the PvPI has set up a toll free number (1800-180-3024) and a mobile application. And in a welcome step, IPC has started collaborating with the Indian Medical Association, aiming to pool in more medical practitioners into the PvPI. After all, medical professionals remain the most critical stakeholder in any pharmacovigilance program, as they are the ones who control both detection and reporting of ADRs.
Currently, the PvPI database has insufficient indigenously generated reports and is dependent on data submitted to the global database by other nations to make conclusive recommendations for many drugs. PvPI outreach efforts are directed towards developing the national database towards self-sufficiency.
Pharmaceutical companies have their major interest in developing and marketing the drug. However, attempts have been made to rope them into drug monitoring as well. In March 2016, the country’s drug regulatory body through a gazette notification directed pharmaceutical companies to set up in-house pharmacovigilance systems to monitor ADRs arising from the use of drugs manufactured or marketed by them, in accordance with global standards. It is noteworthy that various pharmaceutical companies have already initiated the process and have contributed 18.80 per cnet of the ADR reports submitted to PvPI in the year 2015.
It is heartening that after multiple attempts, the current drug-monitoring program of the country is growing at a steady pace. Late to join the global drug-monitoring program actively, much work lies ahead for the PvPI to scale up operations to properly serve the needs of the nation. The program must aim to go beyond making recommendations, and make pharmacovigilance a regular practice for healthcare and allied professionals, starting from including it in the medical training, to formulating a set of comprehensive standard guidelines, similar to Good Pharmaceutical Practices (GVP) of the European Medicines Agency.
Monitoring adverse effects of drugs is indispensable for making informed and safe medical decisions in today’s age, and though the pharmacovigilance program of India is young and developing, it is hoped that with adequate financial and infrastructural support, it will grow to become an integral part of the healthcare system of the country.
(Debaleena Basu is currently pursuing her doctoral degree in Neuroscience at the Indian Institute of Science, Bengaluru. She is a science-writing enthusiast and contributes to the ClubSciWri, an info-blog belonging to the ‘Career Support Group’, a networking, discussion and resource-sharing platform for scientists. She has also written for other portals.)