What pharmacovigilance covers and why it exists
Pharmacovigilance is the science and the activities of detecting, assessing, understanding and preventing the adverse effects of medicines, in on-label and off-label use, across a medicine's whole life, because trials before authorisation cannot reveal every risk that wider use after it brings out. Modern pharmacovigilance began with the thalidomide disaster, and it now reaches beyond medicines to devices, cosmetics, blood and tobacco. Every company that markets a medicine needs a pharmacovigilance system, and the risks it finds are carried forward by risk management and risk minimisation, in which patients take part too.
Definition and objectives
The WHO's historical definition of 1972 describes pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or of any other medicine-related problem. The definition turns on the causal relationship between administering a medicine and the occurrence of an adverse effect, and pharmacovigilance aims to characterise those effects and to understand the risk factors and any circumstances that could be used to prevent a risk from occurring. In short, pharmacovigilance is the science of characterising adverse effects and risks. Detection requires processes and procedures for collecting data on the side effects or adverse events a product causes, assessment asks whether the product or some other factor caused an event, understanding asks what the reasons and contributing factors are, and prevention, much like risk minimisation, looks for ways to prevent the events.
An adverse event is an untoward occurrence, and a risk is defined as any untoward occurrence associated, or suspected to be associated, with the use of a medicinal product. For the sake of an introductory account, a risk and an adverse event can be spoken of as more or less synonymous.
A few years before 2019, European good pharmacovigilance practice legislation pointed out that information on safety and risks can arise within the terms of the authorisation, in on-label use in the authorised indication, and also outside them, in off-label use. It can also arise from other circumstances such as occupational exposure, and pharmacovigilance has to take all of these sources of safety information into account.
The underlying objectives of pharmacovigilance activities are to prevent harm arising from any circumstance of use, medication error, misuse and abuse included; to promote safe and effective use, which includes adequate information and education of the people using the medicine; and to provide timely information on risks to patients, to healthcare professionals and to the public.
Safety before and after authorisation
A clinical trial works with a clean population: participants are selected by a defined set of inclusion and exclusion criteria so that confounders and bias are avoided. Trials run with limited, often small samples, in controlled settings and for relatively short durations, limitations often described as the five toos: too few, too simple, too narrow, too median-aged and too brief. So a trial may recognise only the most frequent adverse effects of a medicine. Trials may miss effects that occur only very rarely, after the product accumulates in the blood or after long-term use; such effects could be better detected after marketing, in real-life settings, and often surface only once the drug is widely used. Safety data from trials may also be insufficient in special populations and on a medicine's abuse potential and the effects of overdose. Certain safety issues may arise only in specific populations, such as older adults, pregnant people or patients taking several medicines, who are frequently under-represented in or excluded from the early phases of clinical trials.
After marketing, the population is heterogeneous: it includes people who would have been excluded from the trials, people taking virtually any concomitant medication and people with diseases besides the one the medicine is meant to treat. So evaluating safety data after marketing can be very challenging, and more complex than in the clean setting of a trial. Both phases matter: the safety knowledge gained in each complements the other, and both have to be taken into consideration.
Effective pharmacovigilance is essential to ensuring the long-term safety and efficacy of medications, particularly in the post-authorisation phase. Comprehensive methods for evaluating drug safety support regulatory compliance and strengthen the prescribing confidence of healthcare providers. As a critical component of regulatory science, pharmacovigilance requires active engagement from regulatory bodies, healthcare professionals and patients alike. Post-marketing surveillance, which may include post-approval surveillance studies, facilitates continued risk management by identifying safety signals not identified during clinical development. A post-marketing surveillance programme sets out to assess and quantify known or suspected issues, to identify and characterise potential new risks and risk factors, and to monitor patterns of use. The data it collects can improve the understanding of real-world use, identify off-label use and potential medication errors, and detect new safety information.
The benefit-risk balance of a medicine can change during its lifecycle, and pharmacovigilance has to be proactive. Its work is not only to react once a side effect has occurred but to characterise in advance what the risks of a medicine are or could be, and to plan adequate measures to characterise them better and to minimise their occurrence or their outcome.
History
The history of pharmacovigilance goes back more than 170 years, to the chloroform-related death of a young English girl in 1848 that led The Lancet to assemble a commission to investigate the safety of anaesthesia.
Thalidomide had been developed in the 1950s as an anticonvulsant; early trials showed it to be unsuitable for that purpose but indicated that it had sedative properties. It was first marketed in Germany in 1957 as an over-the-counter drug considered safe even during pregnancy, was also found to be a highly effective antiemetic alleviating morning sickness, and by 1960 was sold throughout Europe and South America, in Canada and in many other parts of the world. It was used as a hypnotic and antiemetic in the late 1950s and early 1960s and seemed to have few obvious side effects in patients, but as its use spread, some obstetricians began to notice congenital abnormalities in babies born to mothers who had taken it during pregnancy. Given to pregnant women for morning sickness, it was later found to cause congenital malformations.
At the time, drugs were tested in rodents only and did not have to be tested for teratogenic effects. They were not tested for them because they were thought incapable of crossing the placenta. The "clinical trials" of thalidomide in Europe involved distributing more than 2.5 million tablets to about 20,000 patients, including 3,760 women of childbearing age, of whom at least 200 were pregnant; more than 1,000 physicians took part, but few tracked their patients after dispensing the drug. Unknown to the FDA, the drug had already been distributed to 1,200 physicians in the United States, many of them treating pregnant women, and the agency eventually launched a nationwide campaign to recover as much of it as possible.
By about 1960 it had become clear that long-term use of the drug was associated with peripheral neuritis. Its neuropathic side effects were first reported in 1960, in the UK. That year the British Medical Journal published a letter by Leslie Florence about peripheral neuritis in four of his patients, which further nurtured the FDA medical officer Frances Oldham Kelsey's long-held suspicion about the drug's safety. The drug was marketed after tests in animals and sold without prescription; the first affected child was born in the late 1950s, and in 1961 a German paediatrician faced with a sudden increase in cases of phocomelia noted that half of those patients had been exposed to it. Two months passed before the drug was withdrawn from the market and the UK Ministry of Health warned patients to stop taking it, and even then it was not removed from sale; by that point up to 5,000 deformities had been reported in the UK and 10,000 worldwide. Although Germany was already seeing an increase in teratogenic deformities in children born to mothers who had used the drug during pregnancy, no link with thalidomide was established until 1961, when, in response to reports by the German paediatrician Hans-Rudolf Wiedemann and the geneticist and paediatrician Widukind Lenz, the German health authorities took the drug off the market. By that time it had caused the deaths of more than 2,000 children and serious birth defects in about 10,000, most of them in West Germany.
In the wake of the disaster many countries introduced stricter assessment, approval and monitoring procedures for new medicines. The disaster led many countries to set up systems for monitoring the safety of marketed medicines, which encourage health care professionals to report suspected side effects to national regulatory authorities and have been very successful in detecting safety concerns in marketed medicines over the years. In the UK, proposals for new legislation to control medicines were published in 1967 and produced the Medicines Act 1968, which required every medicine already marketed to undergo peer review and then approval or withdrawal. The Act also required every new medicine, from 1971, to undergo a pre-marketing assessment of safety, quality and efficacy by the licensing authority. It controlled the testing and manufacture of drugs for human and veterinary use. In the US, pharmacovigilance is commonly considered to have begun as a separate, identifiable activity with the passage of the Drug Efficacy Amendments of 1962, also known as the Kefauver-Harris Amendments, which were legislated in response to thalidomide.
Modern pharmacovigilance began with thalidomide. The terrible consequences of poor safety monitoring led to the legislation that was the forebear of what was in place by 2018. The tragedy laid the foundation of the ethical and regulatory principles of monitoring drug safety. It cost several thousand lives, and it set off a chain of events involving the World Health Organization and the International Conference on Harmonisation that produced the pharmacovigilance systems in place by 2015. The history of thalidomide emphasises that patients are vulnerable, that a drug's mechanism of action and its related toxicities have to be understood, and that legislation is needed after authorisation as well as before it. The post-marketing arena is vital to the safety of patients and the effectiveness of medicines in real-life settings, and that is achieved by monitoring adverse events and evaluating the benefit-risk profile.
Later drug scandals, from practolol in the 1970s to Pandemrix in 2009, show how vital the drug safety regulations put in place to protect patients have been. The standardising of definitions and processes was taken up by the Council for International Organizations of Medical Sciences (CIOMS), using working groups of experts from government, academia and industry on newly developing issues that include adverse drug reactions, periodic reporting, risk-benefit, safety reporting in clinical trials, signal detection and risk minimisation. Another important, complementary organisation is the International Council for Harmonisation (ICH). International coordination, through the larger regulatory bodies relevant to safety such as ICH and CIOMS and through other organisations, including international professional societies such as the Drug Information Association, aims to ensure that drug safety is monitored appropriately and that relevant safety information is shared between parties immediately to prevent further worldwide issues.
Vigilance beyond medicines
By 2023 pharmacovigilance had grown beyond medicinal products to medical devices, such as a digital thermometer, a digital diagnostic product, an electrocardiograph or blood-pressure monitor that uses software, or a consumer watch that can record an electrocardiogram. Cosmetovigilance, another growing area, covers the side effects of cosmetics and of nutricosmetics, the supplements taken to improve appearance or for a cosmetic effect. Haemovigilance, a very new, niche and growing area, covers the safety of blood and blood products. Gene and precision therapies, which edit or target certain genes, form a very advanced category of products. Some health authorities have also started tobacco vigilance, covering the side effects of tobacco and tobacco-related products such as electronic cigarettes and hookah products, which may have no direct medicinal effect but may be harmful, and which new technology keeps developing and modifying.
Consequences of an inadequate system
Health authorities require every company to have a pharmacovigilance system and to follow the process. A company without one faces measures at several levels, through which an authority can push it to set one up. The first level is a warning or compliance letter, which may be sent to a company that does not actively solicit safety information from the market and from its trials, database it and capture it. The health authority can also call a company representative or senior professional to a discussion, typically, in Europe, the qualified person for pharmacovigilance, who is responsible for all of the company's pharmacovigilance activity. It can raise questions on the company's applications, and it may not approve new applications while products the company already markets are not properly monitored. Where the company still does not act, products already on the market may be recalled. Last, a criminal investigation may be initiated against the company.
These levels have no direct hierarchy: depending on the severity of the issue, an authority can skip straight to the third, fourth or fifth. So any company, even one that markets a single product in one region, needs a foolproof pharmacovigilance process without gaps. Such a process exists to ensure that a disaster like thalidomide does not happen and that problems are captured from the start. Infringement notices for non-compliance, rejection of applications and suspension of the marketing authorisation where considered appropriate are further possible measures.
Pharmacovigilance and risk management
Risk management is a key aspect of pharmacovigilance, the safety monitoring of drugs after their licensing. It aims to understand drugs' benefit-risk profiles better and to minimise their risks to patients, and in 2015 it was a rapidly evolving area. Pharmacovigilance activities lead to risk management, which aims to identify, characterise, prevent or minimise the risks related to the use of a medicinal product. A risk is first detected and characterised through pharmacovigilance activities, and then further characterised, and planned against so as to prevent and minimise it, through risk management.
Pharmacovigilance activities are categorised as routine or additional. Spontaneous reporting, writing the periodic safety update report and signal detection are examples of routine activities. Post-authorisation safety studies are an example of additional activities.
Pharmacovigilance activities also include adverse event and adverse drug reaction reporting and signal evaluation. For some products, adverse event follow-up questionnaires aim to collect more information about adverse events in a structured way. Additional monitoring is an enhanced pharmacovigilance reporting system used, in Europe for example, within the first five years of a marketing authorisation. All pharmacovigilance activities aim to characterise the adverse events and risks of a medicine and to plan adequate risk management measures.
Off-label use
Off-label use cannot really be avoided. Confidence that a medicine is prescribed correctly has to rest on the risk minimisation measures in place, meaning the indication claimed in the summary of product characteristics and the prescribing physician's level of education. Off-label use can be observed through reporting, whether by word of mouth or because adverse events occurred and were, hopefully, reported to the company or to a health authority. The area is a grey zone with a lack of information, but it is still possible, especially for certain medicines, to recognise a pattern of off-label use, and such a pattern needs to be addressed with further risk minimisation measures.
Whether regulatory guidelines address the off-label use of medicines is a complex question without an easy answer, and in 2019 no single guidance could be named as dedicated only to it. The topic appears across a number of guidances according to which aspect a document has to address, among them the GVP guidance on the PSUR and on the RMP, and the European Medicines Agency's website carries documents and questions on it.
Patient involvement in risk minimisation
Patient safety is a fundamental principle of healthcare, in the words of the World Health Organization. Risks associated with therapies are minimised in four key domains: patients and the public, healthcare professionals, systems and practices of medication, and medicines. Of these, the risk mitigation strategies that involve patient empowerment are those of patients and the public, and of healthcare professionals.
In clinical practice, patients can contribute to risk mitigation strategies through reporting systems that communicate any events during medication use to the local health regulatory authorities; through structured interviews with patients and caregivers in research projects run in partnership with universities; through patient representative committees, such as a venous thromboembolism prevention committee, in which patients' perspectives are incorporated into safety initiatives; and through feedback surveys. Quality boards conduct surveys such as the National Inpatient Experience Survey, which gathered feedback from 12,000 patients about their care as inpatients in Irish hospitals, and the Patient Advice and Liaison Service encourages patients and families to suggest service improvements or submit formal complaints.
In the view of one hospital clinical pharmacist, patient-centred risk mitigation strategies are not optional but a necessity for safer healthcare, and these strategies offer medical writers and healthcare professionals valuable tools to help democratise health literacy.
Other senses of risk management
Risk management is also a business practice: to better control risky scenarios, large organisations began to implement it as a new kind of operation. One general definition holds that it is the identification, assessment and prioritisation of risks, risk being defined in ISO 31000 as the effect of uncertainty on objectives, followed by the coordinated and economical application of resources to minimise, monitor and control the probability or impact of unfortunate events, or to maximise the realisation of opportunities. The Professional Risk Managers' International Association, a non-profit organisation founded in 2002, focuses on promoting sound risk management standards and practices globally.
In medical environments the term names a function of the administration of a hospital or other health facility, directed at identifying, evaluating and correcting potential risks that could lead to injury to patients, staff members or visitors and result in property loss or damage. Quality risk management in the pharmaceutical industry is the subject of the ICH Q9 guidance, developed by the ICH's quality expert working group.