Pharmacovigilance and Drug Safety

Adverse Drug Reaction (ADR)
A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. A causal relationship between the medicinal product and an AE should at least be a reasonable possibility.  An ADR in post-marketing situations normally refers to ADRs occurring at therapeutic doses, but for the purposes of reporting any dosage should be considered.

Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered the pharmaceutical product that does not necessarily have to have a causal relationship with the treatment for which the product is used. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A pre-existing condition which, worsened in severity after administration of the product would also be considered as an adverse event.

For clinical studies, the definition of an Adverse Event includes any untoward events occurring at any time after the subject’s formal entry into the study (being after receipt of the signed informed consent) until the follow-up period as defined in the respective study protocol.

Annual Safety Report (ASR)
An aggregate Safety Report in the context of clinical trials, taking into account all newly available safety information produced during a defined reporting period. Where several clinical trials are conducted with the same Investigational Medicinal Product (IMP) the reporter should include a concise global analysis of the actual safety profile of the tested IMP based on the experience for all the clinical trials.

Company Core Data Sheet (CCDS)
This document is prepared by the Marketing Authorisation Holder and contains, in addition to safety information, material relating to indications, dosing, pharmacology and other aspects of the product.

Consumer
A person who is not a healthcare professional such as a patient, lawyer, friend or relative/ parents/ children of a patient.

Expedited Reporting
Notification (submission) of an ICSR in a designated format to the appropriate Regulatory Authorities in compliance with the parameters and timelines specified by legislation and local regulatory guidelines. An expedited report would be an ICSR meeting the criteria for rapid transmission to a Competent Authority.

Healthcare Professional
Within the EU, a healthcare professional would be described as a medically qualified doctor, dentist, pharmacist, nurse or coroner.  When the report originates from a pharmacist or nurse, further information should be sought from a medically qualified doctor responsible for the patient.

Individual Case Safety Report (ICSR)
A report received by a company or agency which describes an adverse event.

Investigator Brochure (IB)
A compilation of the clinical and non-clinical data on the Investigational Medicinal Product relevant to the study of the product in humans.

Investigational Medicinal Product (IMP)
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a different way from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.

Marketing Authorisation (MA)
The approval granted by the Regulatory Authority to market a specific product in a particular country

Marketing Authorisation Holder (MAH)
The company named on the Marketing Authorisation for a specific product in a particular country.

Medicinal Product
A substance or combination of substances presented as having properties for treating or preventing disease in human beings; or a substance or combination which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

Concerned Member State (CMS)
The Regulatory Authority in whose territory a clinical trial with the IMP is being conducted or is involved in the registration of a medicinal product in the EU under Mutual Recognition Procedures, as distinct from the Reference Member State that initiated the Procedure.

Non-interventional Trial
A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods should be used for the analysis of the collected data.

Pharmacovigilance
The process of monitoring, evaluating and improving the safety of medicines. It is carried out by pharmaceutical companies on their products and by government agencies on all medicinal products. Also, the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems (WHO).

Post-authorisation Study
A clinical study conducted within the conditions of the approved Summary of Product Characteristics or under normal conditions of use. A post-authorisation study may also be a Post-authorisation safety study (PASS).

Post-authorisation safety study (PASS)
A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the Marketing Authorisation, with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product.

Risk Management System
A a set of Pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to Medicinal Products, including risk communication and the assessment of the effectiveness of risk minimisation and interventions.

Spontaneous Report
An unsolicited communication by a regulatory authority, healthcare professional, consumer or other person that describes an ADR/AE in a patient administered the Product and which does not derive from a study or any organised data collection scheme.

Signal detection based on spontaneous reporting involves looking for any new patterns or seemingly significant new findings in the safety database. It may be one or more reports showing particularly strong evidence of a previously unknown adverse reaction for that drug, or involving adverse events that are usually caused by drugs, such as aplastic anaemia or toxic epidermal necrolysis. More often, it is a matter of looking for patterns or clusters of reports that stand out from the background. These clusters may be identified by looking at data tables, or – for large databases, such as those held by regulatory authorities or by a company with product with many cases reported – using computerised methods involving statistical disproportion. Examples include the Proportional Reporting Ratio, Bayesian Combination Propagation Neural Network used by the WHO Uppsala Monitoring Centre and the Modified Gamma Poisson Shrinker method used by FDA and MHRA.

Having identified potential tentative signals it is necessary to evaluate them and to consider whether they are real or not. Often, an apparent signal can result just from the disease that the drug is treating – so if a drug is used in patients for the treatment of high blood pressure, it would not be surprising to find reports of high blood pressure itself, and also kidney disease, stroke and heart failure, because these are either contributory or complications of high blood pressure. This is often a difficult process: evaluating signals involves looking at the individual case reports and assessing the strength of causation of the drug in each case. Other sources of safety data are usually also checked at this time – for example, the data from clinical trials and toxicology studies.

It may then be appropriate and necessary to set up a study specifically investigating a particular signal or safety concern. Other possible actions could be to institute a review of the benefits and risks of the product; to suspend or revoke the marketing authorisation; to propose a change to the product information (SPC, labelling); to issue a warning to health professionals in the form of a Dear Health Professional communication; or perhaps just to keep the issue under review. At some point, it may become apparent that the signal was not real, and the issue can be shelved.

Laws

There are EU laws – regulations and directives – on the one hand, and national laws on the other. An EU regulation, when it comes into effect, is in force in all the Member States of the European Union. An EU directive, however, must first be enacted in national law in each EU Member State, within a specified time-frame. In addition to those national laws that promulgate the EU directives, there may also be national laws that concern pharmacovigilance.

The principal EU laws concerning pharmacovigilance are:

• Directive 2001/83, amended by Directive 2004/27. This concerns all medicinal products, although for pharmacovigilance it is most relevant to products authorised by the national, mutual recognition and decentralised procedures. The Member States are the licensing authorities in these procedures.
• Regulation 726/2004. This concerns centrally authorised products. The European Commission is the licensing authority for these products.
• Directive 2001/20. This is the Clinical Trials Directive and includes extensive coverage of pharmacovigilance for interventional clinical trials pre- and post-authorisation.

Guidelines

The EU laws make reference to guidelines drawn up by the European Commission which provide detail and interpretation. These guidelines are not considered to be voluntary – they are mandatory as far as companies are concerned. The guidelines are also directed at regulatory authorities, with detailed requirements for the way that they carry out pharmacovigilance as well. They comprise:

• Volume 9A of the Rules Governing Medicinal Products in the European Community – for post-authorisation pharmacovigilance
• Volume 10 of the Rules Governing Medicinal Products in the European Community. This applies to clinical trials pre- and post-authorisation and incorporates the guideline Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use

In addition to these laws and regulatory guidelines, there are various voluntary guidelines. These are mostly generated by two organizations:

the Council for International Organizations of Medical Sciences (CIOMS)
the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals (ICH).

CIOMS is a body set up under World Health Organization and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others. The main guidelines concern the international reporting form (CIOMS I); periodic safety update reports (CIOMS II); core data sheets (CIOMS III); benefit-risk assessments (CIOMS IV); practical issues in pharmacovigilance (CIOMS V); clinical trial safety data (CIOMS VI); and development safety update reports (CIOMS VII).

Whilst CIOMS guidelines are very influential they are not “official” regulatory guidelines, have no legal force and generally just provide a consensus on good practices and new methodologies.

ICH consists of representatives of the regulatory authorities in the EU, Japan and US, with representatives of the corresponding industry regional organizations and Health Canada and WHO as observers. ICH establishes guidelines applicable to the EU, US and Japan through a series of expert working groups. There is a stepwise development of the guidelines. At Step 4, there is consensus internationally and at Step 5, an agreement by the regulators that they will introduce the guidelines into legislation, although there may be some divergence when these are actually put into effect in the different regions.

The three areas covered by ICH guidelines are Efficacy, Safety and Multidisciplinary. Paradoxically, the “Efficacy” guidelines include clinical (human) safety, whereas the “Safety” guidelines concern only pre-clinical (animal toxicology) safety.

The main guidelines concerning pharmacovigilance are: