Why do we need pharmacovigilance?
In order for a medicine to be authorised by a regulatory authority for use in the UK, the benefits and risks of a medicines are carefully considered. As it is impossible for absolutely all information about a medicine to be known prior to it being authorised, a balance must be struck between making a new medicine available to patients and having adequate information on a product's quality, safety and efficacy. Once a medicine is launched, ongoing safety monitoring is crucial, as at the time the marketing authorisation is granted the medicine will have been tested in a relatively small number of patients for a limited amount of time.
Patients participating in clinical trials are selected carefully and followed closely under tightly controlled conditions. However, once a medicine receives its marketing authorisation, it will be available for use in a wider range of healthcare settings and in patients who may differ from the study population (e.g. ethnicity, age, genetic background and other medical conditions). Patients may also be taking several other medicines and/or using complementary and alternative therapies. It is possible that rarer adverse reactions may only start to be reported once the medicine has been used in a larger number of patients and/or over a long period of time. It is therefore important to be able to identify any new or changing risk associated with a medicine quickly and promptly report them (for example reporting suspected adverse drug reactions to the Yellow Card Scheme).
The legislation concerning pharmacovigilance
Pharmacovigilance legislation, which came into effect in the European Union (EU) in July 2012, was the biggest change to the regulation of human medicines in the EU since 1995. It had implications for marketing authorisation holders (MAHs), as well as for patients, healthcare professionals and regulators; the activities introduced fell into four main areas:
- Collection of key information on medicines, for example the right of individual European citizens to report suspected side effects directly to national medicine regulatory authorities and marketing-authorisation holders was introduced.
- Analysis and understanding of data and information, for example the new legislation introduced the concept of additional monitoring for medicines that are being monitored particularly closely by regulatory authorities. These medicines have an inverted black triangle printed on the product information.
- Regulatory action to safeguard public health, for example the legislation introduced a procedure for the rapid assessment of significant emerging safety issues linked with a medicine.
- Communicating with stakeholders, for example the EMA publishes the agendas and minutes of all of its committees that review the safety of medicines.
This legislation introduced a range of new tasks and streamlined existing responsibilities for regulators and the pharmaceutical industry in the EU and was incorporated into UK law via the Human Medicines Regulation 2012.ii
Once a medicine is on the market, pharmacovigilance activities (performed by both MAHs and regulatory authorities) continually monitor the safety profile of the medicine. It is important to identify new risks (e.g. medication errors) or any changes to the known risks associated with the use of any particular medicine, as quickly as possible, for example identifying and reporting suspected adverse drug reactions to the Yellow Card Scheme. Action can then be taken to minimise the risks of changes in the safety profile, maximise the benefits and promote the safe and effective use of the medicine by patients.
One of the key tools in pharmacovigilance and medicines safety that is used by the Pharmaceutical Industry and Regulatory Authorities in the EU is the Risk Management Plan (RMP). iii
What is a Risk Management Plan?
A Risk Management Plan is written by a pharmaceutical company as part of its application for a marketing authorisation.
RMPs include information on:
- a medicine's safety profile;
- epidemiology of the disease the medicine is used to treat and the patient population;
- how the medicine’s risks will be prevented or minimised in patients;
- what is currently not known about the medicine, e.g. treatment in particular patient population, long term use;
- plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine;
- risk factors for developing adverse reactions to the medicine;
- measuring the effectiveness of risk-minimisation measures.
A RMP aims to identify, characterise, prevent and/or minimise the risk of a medicine. It also identifies information that may be missing and what studies are required to address these data gaps. A RMP is continually updated throughout the life of a medicine so over time knowledge of a medicine’s risk/benefit profile increases and the missing information about a medicine decreases.
RMP summaries written in public-friendly language are published by the European Medicines Agency (EMA) for anyone who wishes to know more about how the risks of a medicine are being managed.iv
A safety concern is an important identified risk, important potential risk or missing information associated with a medicine. A RMP is an important tool for dealing with safety concerns associated with a medicine.
Safety concerns are considered for each individual medicine and suitable risk minimisation measures are selected to take into account the following:v
- seriousness of the potential adverse reaction(s);
- severity (impact on patient) of the reaction;
- preventability of the reaction or the clinical actions required to mitigate the risk;
- indication of the medicine;
- route of administration of the medicine;
- target population for the medicine;
- setting in which a medicine is used e.g. in a clinic or at home.
A safety concern may be addressed using more than one risk minimisation measure, and a risk minimisation measure may address more than one safety concern.
What is a risk minimisation strategy?
A RMP must include a risk minimisation strategy which documents the risk minimisation measures (routine or additional) for a medicine. Risk minimisation can either reduce the severity of the risk when it occurs or reduce its frequency.
Risk minimisation measures may consist of routine or additional risk minimisation activities. Routine risk minimisation activities apply to all medicines and include tools such as the Summary of Product Characteristics (SmPC), the Patient Information Leaflet (PIL), labelling, packaging and legal status of the medicine.
For most medicines, routine risk minimisation is considered sufficient. However for some medicines, additional risk minimisation activities are required to improve the benefit/risk profile. Additional risk minimisation activities can apply to some new medicines as well as to older medicines where a safety issue has been identified. Once a safety issue has been identified, measures are put in place to improve the benefit/risk profile of the medicine.
Additional risk minimisation measures may differ widely in purpose, design, target audience and complexity. The measures may be used to guide the selection of patients who can receive a medicine or identify those patients in whom the medicine is contraindicated. In addition, for patients who are being treated with a medicine, monitoring may be undertaken for important known risks and/or to enable management of an adverse reaction once detected. In addition specific measures may be developed to minimise the risk of medication errors and/or to ensure appropriate administration of the product where it is not feasible to achieve this through the product information and labelling alone, for example training DVDs for healthcare professionals may be provided to ensure correct administration techniques are used.
Examples of additional risk minimisation activities include:
- Educational programmes for HCPs, patients and care givers
These programmes aim to supplement the information in the SmPC and PIL. Materials are prepared that provide clear descriptions of actions to be taken in order to prevent and minimise a safety concern. The overall aim is to improve the use of a medicine by encouraging HCPs and patients to minimise the risk associated with the medicine.
Educational programmes and other risk management materials should not be confused with pharmaceutical industry promotional literature or activities such as journal advertisements and materials aimed at encouraging use or prescription of a particular medicine. Examples of the types of risk management materials that may be available include:
- Alert cards;
- Prescriber/HCP product guides;
- Dosing tools;
- Check lists;
- Dear Healthcare Professional letters;
- Patient screening/monitoring guides.
Risk management materials may be specifically aimed at pharmacists as they are involved in dispensing a medicine or providing alert cards to patients e.g. a pharmacist may support patients taking oral anticoagulant medicines and issue appropriate anticoagulant alert cards.vi
- Patient screening or monitoring
Some medicines require more restrictive types of activities called controlled access programmes. These programmes control the access to a medicine beyond the level described by the SmPC and the PIL. They are used where an important risk has been identified that is associated with significant public health or individual patient impact.
- Controlled access programmes specify requirements that need to be fulfilled before a medicine is prescribed and/or dispensed, for example:
- Specific testing and/or examination of the patient to ensure compliance with strictly defined clinical criteria;
- Prescriber, pharmacist and/or patient documenting their receipt and understanding of information on the serious risk of the product;
- Explicit procedures for systematic patient follow-up through enrolment in a specific data collection system e.g. patient registry;
- Medicines made available for dispensing only to Pharmacies which are registered and approved to dispense the product.
There may also be requirements to test or to monitor a patient in a specific way, for example, monitoring of the patient’s health e.g. an ECG, or laboratory values or other characteristics prior to and/or during treatment, e.g. liver function tests, regular blood tests, pregnancy test (which can be part of a pregnancy prevention programme). Examples of these programmes include the thalidomide pregnancy prevention schemesvii, and controlled access to clozapine via a patient registry and specific patient monitoring criteria.viii
It is important to note that all additional risk minimisation materials and activities require review and prior approval by the MHRA before they can be implemented and used.
How are additional risk minimisation measures communicated?
For some medicines, the MHRA agrees a communication plan with the MAH to educate HCPs and/or patients about the additional risk minimisation measures that have been put in place. Such a plan typically involves the distribution of educational materials or tools, containing the key safety messages to HCPs. Such materials are non-promotional.
Pharmacists may be involved in the further dissemination of educational materials or key safety messages/alert cards to patients or care givers or in educating other HCPs about the safety requirements for medicines.
A direct healthcare professional communication (DHPC) is commonly used to deliver information directly to individual healthcare professionals by a MAH. Such communications are approved by the MHRA and will typically advise if specific actions are needed with regards to a medicine or if any practices need to be changed. The communication may also include copies of additional risk management materials and/or provide information about where to obtain them and where to order further supplies of materials if required.
How can additional risk management materials be accessed?
For some medicines, additional risk minimisation materials can be downloaded via the electronic Medicines Compendium (eMC). ix For some other medicines, an alert card will be provided in the product pack. When a particular medicines risk minimisation materials are not hosted on the eMC or where they are not provided in the product pack, they are available directly from the MAH.
Information may also be communicated and delivered by MAH’s field based teams e.g. sales force for medical scientific liaison teams. In this instance, the activity is strictly non-promotional and is not associated with the promotion of a medicine.
Are risk minimisation activities assessed?
Evaluating the effectiveness and usefulness of additional risk minimisation measures is necessary to establish whether an intervention has been successful or not. If an intervention is shown to be unsuccessful, the evidence should help to determine what corrective actions are necessary.
It is now a legal requirement for MAHs to evaluate their risk minimisation activities to ensure their effectiveness. Some aspects of this evaluation will focus on whether the materials have been received and understood by their target audience and whether any actions have been implemented into clinical practice. Pre- and Post- adverse drug reaction incidence may also be monitored to evaluate the success.
Evaluations may take the form of a survey or study with patients and HCPs. Pharmacists may be approached to participate in these studies, to identify patients, or facilitate audits of pharmacy and patient records.
i Pharmacovigilance. World Health Organisation, Geneva.
ii The Human Medicines Regulations 2012. The Stationery Office, Norwich (2012).
iii Risk-management plans. European Medicines Agency, London.
v Guideline on good pharmacovigilance practices (GVP) Module XVI– Risk minimisation measures: selection of tools and effectiveness indicators (Rev 1). European Medicines Agency, London (2014).
vi Bhandal, S. and Pattinson, J. How to support patients taking new oral anticoagulant medicines. Clinical Pharmacist (2013) 5 268.
vii Thalidomide Celgene™ (Thalidomide). Celgene, Uxbridge (2015).
viii Clozaril Patient Monitoring Service. Novartis, Camberley, UK.
ix Risk Minimisation Materials. Datapharm, Leatherhead, UK.