Pharmacovigilance has been defined by the World Health Organisation as “The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem”

Adverse Events & Adverse Reactions

The ICH E2A guideline describes Adverse Events as any “untoward medical occurrence” which happens to either a patient or a subject in a clinical investigation when a pharmaceutical product has been given to that person¹. This encompasses any signs which are unfavourable and unexpected for the patient or subject, including any abnormal laboratory findings. These could be symptoms or a diseases temporally associated with the use of a medicinal product, and do not have to have been previously associated with that product. Neither do they have to have a known causal relationship with the course of treatment.

ICH E2A characterises Adverse Reactions according to the stage of the medicinal product’s life cycle. If the product has not yet been marketed, Adverse Reactions are any “noxious and unintended responses”¹ to the product at any dose. The effect of this classification is to reasonably establish that a relationship between the product and the reaction “cannot be ruled out”¹. Once the product has been placed on the market, “Adverse Reactions” encompass responses which are again “noxious and unintended” but occur at the established routine dosages which have been defined for use in humans to prevent, diagnose, or treat disease or modify “physiological function”¹. However, some more recent definitions include responses to doses and uses outside those recommended.

Serious Adverse Events (SAEs)

As the names implies, these are “any untoward medical occurrence” that:

• Is fatal
• Is a threat to life
• Results in inpatient hospitalisation
• Prolongs an existing hospital stay
• Results in persistent or significant disability or incapacity
• Results in a congenital anomaly or birth defect

Events that require intervention to prevent the patient or subject experiencing any of the outcomes listed above or otherwise jeopardise the patient are also to be classed as serious, depending on their nature. In some cases expedited reporting will clearly be appropriate. In the EU, suspected transmission of an infectious agent also constitutes a serious adverse event.

Suspected Adverse Drug Reaction (ADRs)

This term is discussed in ICH E2A and ICH E2D, it covers those events where there is the reasonable possibility the event is a direct result of taking the product. Inevitably most serious drug reactions are treated as being “suspected” rather than “confirmed” since they would need some kind of additional evidence, such as “dechallenge and rechallenge” in order to be confirmed. This would mean the patient would take the drug, have the reaction, recover after the drug is withdrawn, and then take the drug again to confirm the reaction. Given the serious nature of such reactions, rechallenge  as a test may be unethical, but it may happen in clinical practice.

Suspected Unexpected Serious Adverse Reactions (SUSARs) and Expected Drug Reactions

Before a product is marketed, a Suspected Unexpected Serious Adverse Reaction is any suspected adverse reaction which is serious and is not consistent with the  information on adverse reactions made available in the current investigator brochure¹. Once a product is marketed, unexpected reactions are are those whose nature or severity is not consistent with the undesirable effects included in the standard product information (Package Insert or Summary of Product Characteristics), although the investigator brochure could also be the reference document for post-marketing studies.

The goal of pharmacovigilance is to protect patients and the public wherever possible and to disseminate knowledge among the relevant professional communities and to patients in order to minimise risk. The information here is provided as a general introduction to the topics and in no way constitutes legal, safety or any other form of professional advice.

Reference and suggested further reading

1. Barton L.Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance. Massachusetts: Jones and Bartlett.

The science of pharmacovigilance is reliant on the collection and accurate processing of data from all over the world. The data is evaluated to produce meaningful drug safety information, from which appropriate actions can be taken as required. This page briefly introduces some major regulatory bodies where the data is held within the European Union (EU).

The Role Of The European Medicines Agency (EMA)

The EMA is the regulatory body with responsibility for all EU member states. It coordinates a network of some 4,000 pharmacovigilance experts from the national regulatory authorities of 31 countries from the EU and European Economic Area (EEA). Its activities include publishing the guidelines which inform Marketing Authorisation Holders (MAHs) and EU clinical trial sponsors on safety, efficacy and quality for both human and veterinary products. The Committee for Medicinal Human Products (CHMP) has been established as the body through which all pharmacovigilance activities for drugs intended for people takes place on behalf of the EMA.

When pharmaceutical companies aim to place any new drug onto an EU market, they must apply for a Marketing Authorisation (MA). There are 4 routes via which this can be done: the National, Centralised, De-centralised and Mutual Recognition procedures. The application for the centralised route must be made directly to the EMA, and evaluation of the quality, efficacy and safety are carried out by an appointed Rapporteur and co-Rapporteur assessor from two of the EU Member State regulatory authorities. Their assessments are then considered by the CHMP which makes a recommendation to the European Commission. Should the application be successful, the European Commission grants a Marketing Authorisation and the product may then be sold in any or all of the 28 EU member states. Many MA applications now take this route, in particular for any medicinal product derived from biotechnology as well as medicines intended for the treatment of:

• Cancer
• Diabetes
• HIV/AIDS
• Neurodegenerative diseases
• Rare diseases

As distinct from the Centralised procedure, individual EU countries may issue National marketing authorisations for medicinal products based on a local assessment of quality, efficacy and safety. Sometimes, a company will use one such National MA as the basis for a Mutual Recognition procedure: that country acts as the Reference Member State and its assessment is evaluated by other EU countries – the Concerned Member States – so that the product can then be marketed in the countries that accept the assessment. The Decentralised procedure is similar – mostly used for generic medicines – it involves a synchronised submission followed by assessment by several EU countries.

Data About Drugs For Rare Diseases

Medicinal products intended for the treatment of rare diseases are termed ‘Orphan Drugs. The Committee for Orphan Medicinal Products (COMP) is responsible for processing any application for an MA for such products.

Data About Herbal Medicines

The Committee on Herbal Medicinal Products (HMPC) reviews applications for marketing of herbal medicinal products intended for sale within the EU.

EU Safety databases

From November 2017, all marketed product serious and non-serious Individual Case Safety Reports (ICSRs) occurring within the EEA will be reported directly to EudraVigilance by MAHs and other stakeholders under simplified centralised reporting.

Regulatory authorities or, in some instances such as the Netherlands, independent national pharmacovigilance centres, hold databases on post-marketing spontaneous and clinical trial adverse reactions.

The EMA manages the Eudravigilance database which is a repository for adverse reaction data from post-marketing spontaneous reports and of serious adverse reactions from clinical trials from across the EU.

The Flow Of Information

Reports of Adverse Reactions may be generated by individual doctors, nurses, other healthcare professionals, pharmacists or patients themselves or their friends, relatives or others. They may be submitted to national regulatory authorities, where appropriate, the independent national pharmacovigilance centres, to regional centres in various countries or to the pharmaceutical company.

Pharmaceutical companies must operate a suitable safety database to allow for timely and accurate reporting in the correct format to the national authorities and EMA.

Within pharmacovigilance, adverse reactions that occur within a short time of stopping or starting a particular drug are relatively easy to detect. They are often more readily suspected because of the close temporal relationship and are associated with a higher degree of biological and pharmacological plausibility.

Pharmacovigilance work to detect problems which occur with a longer latency period involves cases where the cause of the reaction is far more difficult to ascertain.

There are a variety of reasons for this phenomenon. It could be that medical records are not available, or that the patient cannot accurately remember how and when they were taking the product – and how and when they stopped. The relationship between the adverse event and the responsible medicine is less likely to be suspected by either the patient or their health professional, as there may be no clear logical, pharmacological or biological relationship apparent between taking the drug and the reaction arising. Suspicions between an Adverse Reaction occurring with a long latency period for a particular drug might only be detected by epidemiological means.

Well established drugs may have the potential to cause serious problems after many years on the market

There have been cases where a drug has been very well established on the market before the potential to provoke the Adverse Reaction has been detected. A robust pharmacovigilance system is essential to ensure that manufacturers and drug regulators are correctly monitoring, evaluating and processing any reports associated with even the longest established products, even after the patent has expired. An example here could be when various pharmaceutical companies that manufacture generic products have placed differing versions of a long-established drug onto the market and there could be reactions reported with just one version of the product, or if there were problems with quality in a batch from a manufacturer – whether a generic or an innovator company – that resulted in adverse reactions.

Examples of known adverse reactions associated with longer latency periods

An example could be the drug isoniazid, which has been estimated to have a latency period of around a year when considering unpredictable immune-mediated hypersensitivity reactions or idiosyncratic reactions. There are other examples of even longer latency periods. Practolol was a beta adrenergic receptor blocking agent which was found to provoke an oculomucocutaneous syndrome. It was withdrawn from sale in 1975 following a series of reports; the average latency period for this problem has since been estimated at over four years.

Particular therapeutic approaches may also present a risk of long latency adverse reactions or delay in detection. Gene therapy may represent one example, whereby the permanent changes to recipient cells may be associated with toxicities which are detected many years later. There may also be cases where viral vectors are used, raising the possibility of whether the potential exists for a latent infection to clinically manifest itself some years later. Some antiretrovirals have been found to be associated with multiple late onset problems related to toxicity. Long term follow up clinical trials are of paramount importance; controlled comparisons and epidemiological methods such as prospective cohort studies may be useful here.

Problems affecting the next generation not the patient

There have also been Adverse Reactions which occurred not for the patient who took the drug, but for their adult children. This was the scenario presented by Diethylstilbestrol (DES) which was prescribed as an oestrogen intended to prevent miscarriage. Used in the USA from 1941, it was not until 1970 that suspicions were raised over a series of cases of a rare vaginal cancer (clear cell adenocarcinoma, abbreviated to CCA). This disease is associated with patients in their seventies but was nonetheless being diagnosed in patients aged between 14 and 22 years old. A case control study finally confirmed the suspicion in 1971, some thirty years after the drug was placed onto the market: the cancer was associated with exposure of the embryo to stilbestrol taken by the mother. It was also later found that there were other serious problems associated with taking the drug, including malformations of the cervix and uterus; decreased fertility; ectopic pregnancies; and higher incidences of spontaneous abortions and preterm births.

Adverse reactions that mimic natural disease

It can be particularly difficult to detect adverse reactions that just represent an increase in frequency over the “normal” incidence of a disease. For example, if a medicine causes heart attacks but is used mostly in an elderly population (for example for treating arthritis), it could be difficult to distinguish what is caused by the drug from what would be expected to occur anyway in these patients without the drug. This is the situation with rofecoxib (Vioxx®) – a drug that was introduced for the treatment of arthritis but was found to have adverse effects on the heart.

False alarms – examples where suspicions around adverse reactions were not found to be associated with medicinal products

One contrary example of why a robust drug safety system must be operational during such long periods of time is the case of Bendectin™. It was prescribed for morning sickness in pregnancy over a 27 year period, by some 20 to 40% of all pregnant women in the USA. When the product was subsequently suspected to cause congenital abnormalities (as had been the case with thalidomide) it was withdrawn from sale. However, a series of case control studies did not find any relationship between the drug and the abnormalities. Given the widespread concern over the potential adverse reaction however, this product was not returned to the USA market even after pharmacovigilance scientists concluded that the suspicions were unfounded, although it was made available as a constituent of some medicines in Europe.

Pharmacovigilance work does not stop once a drug has been on the market for any number of years, nor when a patent simply expires. Every medicine on sale needs to be constantly monitored by drug safety systems supported by services that are responsive, comprehensive, legally compliant and effective – at every stage of the drug’s life cycle.

Reference and suggested further lay reading

1. Barton L. Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance.
Massachusetts: Jones and Bartlett.