Eur J Clin Pharmacol (2008) 64:743–752DOI 10.1007/s00228-008-0475-9 Pharmacovigilance: methods, recent developmentsand future perspectives L. Härmark & A. C. van Grootheest Received: 7 February 2008 / Accepted: 14 February 2008 / Published online: 4 June 2008 Background Pharmacovigilance, defined by the WorldHealth Organisation as ‘the science and activities relating The field of drug safety has been receiving a great deal of to the detection, assessment, understanding and prevention attention lately. Almost weekly, tabloids as well as scientific of adverse effects or any other drug-related problem’ plays journals publish articles on drugs that cause unexpected a key role in ensuring that patients receive safe drugs. Our adverse drug reactions (ADRs). These articles have the knowledge of a drug’s adverse reactions can be increased unfortunate result of evoking apprehension in both patients by various means, including spontaneous reporting, inten- and health professionals regarding the use of these drugs. A sive monitoring and database studies. New processes, both more serious consequence may be that the patient stops taking at a regulatory and a scientific level, are being developed the prescribed medication, which may lead to an even more with the aim of strengthening pharmacovigilance. On a serious situation than the ADR he was initially concerned regulatory level, these include conditional approval and risk about. Pharmacovigilance, defined by the World Health management plans; on a scientific level, transparency and Organisation (WHO) as ‘the science and activities relating to increased patient involvement are two important elements.
the detection, assessment, understanding and prevention of Objective To review and discuss various aspects of phar- adverse effects or any other drug-related problem’ plays a macovigilance, including new methodolgical developments.
vital role in ensuring that doctors, together with the patient,have enough information to make an educated decision when Keywords Drug regulation . Drug safety .
it comes to choosing a drug for treatment.
Intensive monitoring . Pharmacovigilance .
The aim of this review is to provide a summary of the most common methods used in pharmacovigilance toguarantee the safety of a drug. Recent developments inpharmacovigilance as well as future needs are discussed.
As an introduction to the sort of problems pharmaco- vigilance has to face, a few examples of recent safetyconcerns and the action taken are briefly described.
L. Härmark (*) A. C. van Grootheest Netherlands Pharmacovigilance Centre Lareb,Goudsbloemvallei 7, The withdrawal of rofecoxib directed renewed attention to 5237 MH ’s-Hertogenbosch, The Netherlandse-mail: [email protected] drug safety. The decision to withdraw rofecoxib was madeafter the safety monitoring board of the APPROVe trial found an increased risk of cardiovascular (CV) events in Department of Pharmacy: Pharmacotherapy and Pharmaceutical Care, patients treated with rofecoxib compared to placebo University of Groningen,Groningen, The Netherlands The events leading to the withdrawal of rofecoxib, and what has happened since the withdrawal, has been heavily criticised on a number of points –Firstly, the FDA uses only a limited number of data sources (clinical Another association that has been much debated the last trials, spontaneous reporting) when it comes to assembling year is the association between rosiglitazone and cardiac information on the safety of a drug. Secondly, the FDA has effects. In June 2007 a meta-analysis was published no control over the performance of post-marketing safety wherein the use of rosiglitazone was linked to an increased studies. The majority of post-marketing study commitments risk of myocardial infarction and death from cardiovascular are never initiated, and the proportion of post-marketing causes The results of this one meta-analysis kindled a safety studies (phase 4 studies) that were completed growing debate on the safety of the drug [–], and new declined from 62% between 1970 and 1984 to 24% studies were rapidly published with the aim of rejecting or between 1998 and 2003. Thirdly, the FDA has no authority confirming the results of the first study , ]. Both the to take direct legal action against companies that do not US Food and Drug Administration (FDA) and the Europe- fulfil their post-marketing commitments ]. Some critics an Medicines Agency (EMEA) have now concluded that also claim that the FDA has become too close to the the benefits of rosiglitazone outweigh its risks within the industry that they are supposed to regulate and that a sepa- framework of its approved indications , However, ration between regulatory duties and the post-marketing constant revision/updating of product information and a surveillance activities is desirable ]. In response to the continued monitoring of this ADR are necessary.
criticism, the Centre for Drug Administration (CDER) at A more recent safety concern is the association between the FDA asked the Institute of Medicine (IOM) to assess aprotinin and increased mortality. In 2006, a study based on the US drug safety system. In September 2006, the IOM observational data was published by Mangano et al. in which released the committee’s findings and recommendations these authors questioned the safety of aprotinin On in a report 'The future of drug safety: promoting and November 21, 2007, aprotinin was withdrawn from the protecting the health of the public’ [The main message market in the European Union based on data from the BART in this report is that the FDA needs to follow the safety of a clinical trial showing increased mortality for patients receiving drug during its whole life cycle. This life-cycle approach aprotinin ]. Table provides an overview of recent major includes identifying safety signals, designing studies to drug safety issues and the evidence that led to their discovery.
confirm them, evaluating benefits as well as risks, using Whenever a drug safety issue occurs, the first reaction is risk–benefit assessments to integrate study results and to search for a reason of why such a thing could happen. In communicating key findings to patients and physicians the case of rofecoxib, this led to a critical evaluation of the current methods and mechanisms available for safeguarding In Europe the withdrawal of rofecoxib led to an assessment of the pharmacovigilance system in the differentEuropean Union member states, which was published in Regulatory action after rofecoxib withdrawal March 2006. The report ‘Assessment of the EuropeanCommunity System of Pharmacovigilance’ highlighted the In the aftermath of the withdrawal of rofecoxib, the FDA strengths and weaknesses of the European pharmacovigi- and the current system of post-marketing surveillance was lance system. The report’s recommendations focussed on Table 1 Drug safety concerns that have arisen in Europe since 1995 and evidence for thesea QT prolongation; cardiac arrhythmias Spontaneous ADRs Patient registration licences subsequently cancelled Hormone replace therapy CVS risk; cancer long term Epidemiological studies Warnings and restriction of indication Warnings accompanied by clinical guidance SSRI, selective serotonin reuptake inhibitors, CVS, cardiovascular safety; ADR, adverse drug reactiona From Pharmacovigilance; risk managementa European regulatory view by J.M Raine. Copyright: John Wiley & Sons Limited, 2007Reproduced with permission of the publisher the breadth and variety of data sources, the pro-active use post-marketing surveillance because they are able to of registration, the speed of decision-making, the impact of generate hypotheses that will become starting points for regulatory action and communication, compliance by analytical studies [Two forms of descriptive studies— marketing authorisation holders and general principles of spontaneous reporting and intensive monitoring—will be quality management and continuous quality improvement discussed here. Analytical studies can be conducted using a variety of approaches, including case–control studies,cohort studies and clinical trials. In order to be able toconduct retrospective cohort and case–control studies, datawhich have been collected in a reliable and routine manner needs to be available. To provide an example of suchstudies, we describe here two European databases fre- The activities undertaken in the name of pharmacovigilance quently used for analytical studies, the General Practitioners can be roughly divided into three groups: regulatory, Research Database (GPRD) in the UK and the PHARMO industry, and academia. Regulatory pharmacovigilance is Record Linkage System in the Netherlands.
driven by the aim to provide drugs with a positive benefit–harm profile to the public. Some of the problems related to regulatory post-marketing surveillance will be discussed inthis context, followed by a description of the methods used In 1961, a letter from the Australian physician WG to detect new ADRs and a discussion of the pros and cons McBride was published in Lancet. In this letter, he shared his observation that babies whose mothers had usedthalidomide during pregnancy were born with congenital Clinical trial data insufficient to evaluate drug risk abnormalities more often than babies who had not beenexposed to thalidomide in utero ]. In the years to come it The main method currently used to gather information on a became evident that thousands of babies had been born drug in the pre-marketing phase is to conduct a clinical with limb malformations due to the maternal use of trial. Pre-marketing clinical trials can be divided into three thalidomide. In order to prevent a similar disaster from phases. Phase III studies are often double blind randomised occurring, systems were set up all over the world with the controlled trials; these are considered to be the most aim of regulating and monitoring the safety of drugs.
rigorous approach to determining whether a cause–effect Spontaneous reporting systems (SRS) were created, and relationship exists between a treatment and an outcome.
these have become the primary method of collecting post- However, when it comes to monitoring the safety of a drug, marketing information on the safety of drugs. The main this study design is not optimal. Due to the limited number function of SRS is the early detection of signals of new, of patients participating, it is generally not possible to rare and serious ADRs. A spontaneous reporting system identify ADRs that occur only rarely. The relatively short enables physicians and, increasingly more often, pharmacists duration of clinical trials makes it difficult to detect ADRs and patients to report suspected ADRs to a pharmacovigi- with a long latency. Another limitation of clinical trials is lance centre []. The task of the pharmacovigilance the population in which a drug is tested. The characteristics centre is to collect and analyse the reports and to inform of the participants do not always correspond to the stakeholders of the potential risk when signals of new characteristics of the population in which it will later be ADRs arise. Spontaneous reporting is also used by the used; consequently, it may be difficult to extrapolate the pharmaceutical industry to collect information about their results obtained from clinical trials to the population at drugs. By means of a SRS it is possible to monitor all drugs large [This is especially true for the elderly, for women on the market throughout their entire life cycle at a or for people belonging to a minority ethnic group , ].
relatively low cost. The main criticism of this approach is In order to study rare ADRs, ADRs with a long latency and the potential for selective reporting and underreporting [ ADRs in specific populations, careful monitoring of the In a review article, Hazell and Shakir investigated the drug in the post-marketing phase is essential.
magnitude of underreporting in SRS and determined that Post-marketing studies can be descriptive or analytical.
more than 94% of all ADRs remain unreported [ Descriptive studies generate hypotheses and attempt to Underreporting can lead to the false conclusion that a real describe the occurrence of events related to drug toxicity risk is absent, while selected reporting of suspected risks and efficacy. Analytical studies test hypotheses and seek to may give a false impression of a risk that does not exist.
determine associations or causal connections between However, underreporting and selective reporting can also observed effects and particular drugs, and to measure the been seen as advantages. Because only the most severe and size of these effects. Descriptive studies are widely used in unexpected cases are reported, it is easier to detect new signals of ADRs because the person reporting the reaction strong relationships in the data are highlighted relative to has already pinpointed what may be a new safety issue.
general reporting of suspected adverse effects. The WHO Against this background, the system should perhaps be Collaborating Centre for International Drug Monitoring called 'concerned reporting' instead of spontaneous report- uses this method for data mining ]. A related approach is ing, seeing as those reporting the issues are highly selective the Multi-Item Gamma Poisson Shrinker (MGPS) used by of what they are reporting [With a SRS, it is not the FDA for data mining of their spontaneous report’s possible to establish cause–effect relationships or accurate database. The MGPS algorithm computes signal scores for incidence rates; it is also not possible to understand risk pairs, and for higher-order (e.g. triplet, quadruplet) factors or elucidate patterns of use. Although critics say that combinations of drugs and events that are significantly spontaneous reporting is not the ideal method for monitor- more frequent than their pair-wise associations would ing the safety of drugs, it has proven its value throughout predict ]. All data-mining approaches currently cannot the years. Eleven products were withdrawn from the UK distinguish between associations that are already known and U.S. markets between 1999 and 2001. Randomised and new associations. Moreover, clinical information trial evidence was cited for two products (18%) and described in the case reports is not taken into account; comparative observational studies for two products (18%).
consequently, there is still the need for a reviewer to Evidence from spontaneous reports supported the with- drawal of eight products (73%), with four products (36%)apparently withdrawn on the basis of spontaneous reports only. For two products, the evidence used to support theirwithdrawal could not be found in any of the identified In the late 1970s and early 1980s a new form of active documentation ]. Of nine recent significant drug safety surveillance was developed in New Zealand (the Intensive issues handled in the European Union since 1995, six were Medicines Monitoring Programme) and the UK (Prescription detected by spontaneous reports (Table ), which demon- Event Monitoring). These intensive monitoring systems use strates the strength of spontaneous reporting in detecting prescription data to identify users of a certain drug. The prescriber of the drug is asked about any adverse eventoccurring during the use of the drug being monitored. These data are collected and analysed for new signals. Themethodology of these intensive monitoring systems have In the past, signal detection in spontaneous reporting has been described in depth elsewhere [–].
mainly occurred on the basis of case-by-case analyses of The basis of intensive monitoring is a non-interventional reports. In recent years, however, data mining techniques observational cohort, which distinguishes it from spon- have become more important. The term ‘data mining’ refers taneous reporting because the former only monitors to the principle of analysing data from different perspec- selected drugs during a certain period of time. Through its tives and extracting the relevant information. Algorithms non-interventional character, intensive monitoring provides are often used to determine hidden patterns of associations real world clinical data involving neither inclusion nor or unexpected occurrences—i.e. signals—in large data- exclusion criteria throughout the collection period. It is bases. Although the methodology of the various data unaffected by the kind of selection and exclusion criteria mining methods applied in pharmacovigilance differ, they that characterise clinical trials, thereby eliminating selection all share the characteristic that they express to what extent bias. Another strength of the methodology is that it is based the number of observed cases differs from the number of upon event monitoring and is therefore capable of identi- fying signals for events that were not necessarily suspected Several approaches of data mining are currently in use.
as being ADRs of the drug being studied. Intensive Proportional reporting ratios (PPRs), compare the pro- monitoring programmes also enable the incidence of portion of reports for a specific ADR reported for a drug adverse events to be estimated, thus enabling quantification with the proportion for that ADR in all other drugs. The of the risk of certain ADRs. This approach, however, also calculation is analogous to that of relative risk. Using the has recognised limitations. The proportion of adverse same information, it is also possible to calculate a ‘reporting effects that go unreported to doctors is unknown. The studies also produce reported event rates rather than true The Bayesian confidence propagation neural network incident rates. This is the same for all studies based on (BCPNN) method is used to highlight dependencies in a medical record data, including computer databases and data set. This approach uses Bayesian statistics imple- record linkage. There is no control group in standard mented in a neural network architecture to analyse all intensive monitoring studies, and the true background reported ADR combinations. Quantitatively unexpectedly incidence for events is therefore not known ].
Although the intensive monitoring methodology was developed more than 20 years ago, this methodology hasreceived renewed interest in the last years. In the European In the early 1990s, the PHARMO system of record linkage Commission consultation ‘Strategy to better protect public was developed in The Netherlands. PHARMO links health by strengthening and rationalising EU pharmacovig- community pharmacy and hospital data within a specific ilance’ intensive monitoring is mentioned as one tool that region on the basis of patient birth date, gender and GP can improve the pharmacovigilance system ].
code. The system now includes drug-dispensing recordsfrom community pharmacies and hospital discharge records of about 2 million people in the Netherlands. The datacollection is longitudinal and goes back to 1987. More In order to test a hypothesis, a study has to be performed.
recently, PHARMO has also been linked to other data, such The study can be conducted using a variety of methods, as primary care data, population surveys, laboratory and including case–control studies and cohort studies. The genetic data, cancer and accident registries, mortality data limitations of these methods include power considerations and economic outcomes. The system has well-defined and study design. In order to be able to conduct retro- denominator information that allows incidence and preva- spective cohort and case–control studies, data which have lence estimates and is relatively cheap because existing been collected in a reliable and routine fashion needs to be databases are used and linked. The PHARMO database is available. The General Practice Research Database (GPRD) used for follow-up studies, case–control studies and other and the PHARMO Record Linkage System, which will be analytical epidemiological studies for evaluating drug- described in further detail in the following sections, were induced effects. In the past the database has been used for chosen here because they represent two different types of studies on drug utilisation, persistence with treatment, European databases. Other database- and record linkage systems are available for research purposes in both Europeand in North America [ Pharmacovigilance and the methods used need to continue Virtually all patient care in the UK is coordinated by the to develop in order to keep up with the demands of society.
general practitioner (GP), and data from this source provide an In recent years, three publications have been of utmost almost complete picture of a patient, his illnesses and importance in terms of providing guidance on the future of treatment. In any given year, GPs, who are members of the pharmacovigilance. The first is the Erice Declaration on GPRD, collect data from about 3 million patients (about 5% of transparency, which was published in 1997 In this the UK population). These patients are broadly representative declaration, pharmacovigilance experts from all over the of the general UK population in terms of age, sex and world, representing different sectors, emphasise the role of geographic distribution. The data collected include demo- communication in drug safety with the following statements: graphics (age and sex), medical diagnoses that are part of – Drug safety information must serve the health of the routine care or resulting from hospitalisations, consultations or emergency care, along with the date and location of the event.
– Education in the appropriate use of drugs, including There is also an option of adding free text, referral to hospitals interpretation of safety information, is essential for the and specialists, all prescriptions, including date of prescrip- public at large, as well as for health care providers tion, formulation strength, quantity and dosing instructions, – All the evidence needed to assess and understand risks indication for treatment for all new prescriptions and events leading to withdrawal of a drug or a treatment. Data on – Every country needs a system with independent expertise vaccinations and miscellaneous information, such as smoking, to ensure that safety information on all available drugs is height, weight, immunisations, pregnancy, birth, death, date adequately collected, impartially evaluated and made entering the practice, date leaving the practice and laboratory – Innovation in drug safety monitoring needs to ensure A recent review of protocols using GPRD data showed that emerging problems are promptly recognised and that the database is used for pharmacoepidemiology (56%), efficiently dealt with, and that information and solutions disease epidemiology (30%) and, to a lesser degree, drug utilisation, pharmacoeconomics and environmental hazards.
There have been over 250 publications in peer-reviewed It is believed that these factors will help risks and benefits to be assessed, explained and acted upon openly and in a spirit that promotes general confidence and trust.
Strategy’. In July 2007, the EMEA published a document in This declaration was followed in 2007 by the Erice which they discussed the achievements booked to date.
Manifesto for global reform of the safety of medicines in These achievements included the implementation of legal patient care ]. The Erice Manifesto specifies the chal- tools for monitoring the safety of medicines and for regulatory lenges which must be addressed to ensure the continuing actions. Particular emphasis was placed on: development and usefulness of the science, in particular: 1. Systematic implementation of risk management plans – The active involvement of patients and the public in the Strengthening the spontaneous reporting scheme core debate about the risks and benefits of medicines, through improvements of the EudraVigilance database and in decisions about their own treatment and health 3. Launching the European Network of Centres for – The development of new ways of collecting, analysing Pharmacoepidemiology and Pharmacovigilance (ENCePP) and communicating information about the safety and project to strengthen the monitoring of medicinal products effectiveness of medicines; open discussion about it 4. The conduct of multi-centre post authorisation safety – The pursuit of learning from other disciplines about 5. Strengthening the organisation and the operation of the how phamacovigilance methods can be improved, alongside wide-ranging professional, official and public In the course of the next 2 years, two main areas will be covered by the European Risk Management Strategy: The creation of purposeful, coordinated, worldwide further improving of the operation of the EU Pharmaco- support amongst politicians, officials, scientists, clini- vigilance System and strengthening the science that cians, patients and the general public, based on the underpins the safety monitoring for medicines for human demonstrable benefits of pharmacovigilance to public In December 2007, a public consultation ‘Strategy to The third article that has had a profound impact on how Better Protect Public Health by Strengthening and pharmacovigilance should work in the future is the article Rationalising EU Pharmacovigilance’ was published on published in 2002 by Waller and Evans in which they give behalf of the European Commission. This document con- their view on the future conduct of pharmacovigilance. The tains legislative strategy and key proposals for legislative key values that should underpin pharmacovigilance are changes within the European Union. Areas where excellence (defined as the best possible result), the legislative changes are needed include: fast and robust scientific method and transparency. The paper defines five decision-making on safety issues, clarification of roles and elements that are considered to be essential for achieving responsibilities for industry and regulators, strengthening of excellence. Three of these are: process-oriented best the role of risk-management planning, improvement of the evidence, robust scientific decision-making and effective quality if of non-interventional safety studies, simplification tools to deliver protection of public health. The other two of ADR reporting, including introducing patient reporting, elements, scientific development and audit, underpin these strengthening of medicine safety, transparency and com- processes, recognising that excellence cannot be achieved munication, including clearer safety warnings in the prod- uct information to improve the safe use of medicines In the past, pharmacovigilance has been most concerned with In the USA, the FDA has had a difficult time since the finding new ADRs, but Waller and Evans suggest that withdrawal of rofecoxib. The main concern is that the FDA pharmacovigilance should be less focused on finding harm is not able to protect the public from drug risks as and more focused on extending knowledge of safety ]. In efficiently as it might. In February 2007, on the basis of recent years, regulatory agencies have been reforming their the IOM report, the FDA announced several initiatives systems in order to keep pace with the developments in designed to improve the safety of prescription drugs [ pharmacovigilance, with the focus on being more pro-active.
These initiatives fall into four main categories. The first isincreasing the resources for drug safety activities. Perceiving the agency as being overly dependent on industry funding,some observers propose eliminating user fees. The second In 2005, a document was drafted by the Heads of the category of proposed reform is new authority for the FDA; Medicines Agencies called ‘Implementation of the Action the agency needs regulatory tools to help assure drug safety.
Plan to Further Progress the European Risk Management This authority would be exercised through a required risk evaluation and mitigation strategy, including measures such there is a specific patient need. Examples include products as prescribing restrictions, limits on direct consumer mar- for seriously debilitating or life-threatening diseases, medic- keting and requirements for post-marketing studies. The inal products to be used in emergency situations in response FDA could impose monetary penalties for non-compliance.
to public threats and products designated as orphan A third aspect of the reform is the improvement of post- medicinal products. A conditional marketing authorisation marketing surveillance. A routine systematic approach to is granted in the absence of comprehensive clinical data active population-based drug surveillance that could identify referring to the safety and efficacy of the medicinal product.
potential safety problems is needed. Finally, changes in the However, a number of criteria have to be met including: FDA management practices and safety supervision are 1. A positive risk–benefit balance of the product 2. Likeliness that the applicant will be in a position to In May 2007, the U.S. senate passed its version of reform for the FDA. The senate proposed that the Prescription Drug User Fee Act, which allows the pharma- 4. The benefit of the immediate availability of the ceutical industry to pay money directly to the FDA, should medicinal product to public health outweighing the increase their payments to the FDA by close to U.S. 400 risk inherent in the absence of additional data million dollars. Furthermore, this reform would give theFDA new authority to order companies to undertake formal Conditional marketing authorisations are valid for 1 safety studies of drugs that are being marketed and to fine year, on a renewable basis. The holder is required to those who do not honour their post-marketing commit- complete ongoing studies or to conduct new studies with ments, However when it came to changing the structure of the objective of confirming that the risk–benefit balance is the FDA, the proposal to create an independent office for positive. In addition, specific obligations may be imposed the monitoring of the safety of drugs was rejected by a in relation to the collection of pharmacovigilance data.
The authorisation is not intended to remain conditionalindefinitely. Rather, once the missing data are provided, it should be possible to replace it with a formal marketingauthorisation. The granting of a conditional marketing authorisation will allow medicines to reach patients withunmet medical needs earlier than might otherwise be the The Erice Declaration as well as Waller and Evans case and will ensure that additional data on a product are ], stated that transparency is important for the future of generated, submitted, assessed and acted upon.
pharmacovigilance. In the last few years transparencyaround ADRs has increased. The registration of clinical trials will allow the necessary tracking of trials to ensurefull and unbiased reporting for public benefit ]. A Another step in a more pro-active post-marketing surveil- lance is the introduction of risk management plans (RMPs) ]. Such RMPs are being set up in order to identify, characterise, prevent or minimise risk relating to medicinal taining the data from the spontaneous reporting system products, including the assessment of the effectiveness of those interventions. A RMP may need to be submitted atany time in a product’s life cycle, for example, during both the pre-authorisation and post-authorisation phases. A RMPis required for all new active substances, significant Both the FDA report and the report from the European changes in established products (e.g. new form/route of Union described earlier emphasise that compliance by administration), established products introduced to new marketing authorisation holders needs to be improved when populations, significant new indications or when an it comes to additional post-marketing studies. A possible solution to this problem would be a time-limited conditional The EU Risk Management Plan consists of two parts: the approval, which would place pressure on the manufacturers first part contains a 'safety specification and a pharmaco- to conduct and report additional safety studies ].
vigilance plan' and the second part contains an evaluation Within the European Union, the EMEA has introduced a of the need for risk minimisation activities and, if conditional marketing authorisation. The Committee for necessary, a risk minimization plan. The safety specifica- Medicinal Products for Human Use (CHMP) delivers a tion contains a summary of what is known and what is not conditional marketing authorisation for products where known about the safety of the product. This specification encompasses the important identified risk and any infor- mation and outstanding safety questions which warrantfurther investigation in order to refine the understanding of On a regulatory level, progress has been made during the benefit–risk during the post-authorisation period.
past few years. However, the results of these changes have A risk minimization plan is only required in circum- yet to become apparent and, therefore, it has not yet been stances where the standard information provision, by means proven if these developments have contributed to better of a medicine’s summary of product characteristics, is pharmacovigilance conduct. In order to further prove considered inadequate. Insufficient patient information leaf- pharmacovigilance as a science, it is essential that academia lets or inadequate labelling of the medicine are additional develops new methods which can strengthen the current reasons for drawing up a risk minimization plan. Where a risk minimization plan is considered necessary, both routine Pharmacovigilance as we know it today has been about and additional activities are to be included. Some safety detecting new ADRs and, if necessary, taking regulatory concerns may have more than one risk minimisation activity, actions needed to protect public health—for example, by each of which should be evaluated for effectiveness.
changing the summary of product characteristics (SPCs) or Many RMPs have already been established; however, to withdrawing the drug from the market. Little emphasis has date, no quantitative or qualitative reports have been released been put into generating information that can assist a by the EMEA. Information to the public about RMPs has healthcare professional or a patient in the decision-making also been scarce. If RMPs are to take an important place in process of whether of not to use a drug. The gathering and pharmacovigilance, they need to be made public and easily communication of this information is an important goal of accessible to scientists, professionals and patients.
Active surveillance is necessary to receive information about the safety of a drug at an early stage. Whendeveloping new methods for active post-marketing surveil- Another important development is the recognition of the lance, one has to bear in mind the importance of being able patient as an important player in pharmacovigilance.
to gather information in a timely manner. Spontaneous Patients are the users of drugs, and it is their use of a reporting has indeed been shown to be a useful tool in drug in a safe manner is the ultimate goal of pharmaco- generating signals, but the relatively low number of reports vigilance activities. In an increasing number of countries received for a specific association makes it less useful in patients are now allowed to report ADRs to the spon- identifying patient characteristics and risk factors that will taneous reporting system. The European Commission contribute to the occurrence of an ADR in a certain person.
acknowledges the role of the patient in spontaneous This information is essential when it comes to a healthcare reporting [Patients and patient organisations are provider recommending whether or not a particular patient becoming increasingly more involved in pharmacovigi- should use the drug in question. Furthermore, when facing lance, especially when it comes to risk communication an ADR, questions that patients as well as the treating physician can ask are: will this ADR disappear?; how long After introducing patient reporting in the spontaneous will it take before it does?; what treatment is needed? reporting scheme in 2004, ], the Netherlands Pharma- None of the main methods used today in post-marketing covigilance Centre Lareb took patient reporting one step surveillance can provide an answer to these questions. It is further and introduced, in 2006, an intensive monitoring therefore important to develop methods that can follow a programme using patients as a source of information. The patient using a particular drug over time, as the information Lareb intensive monitoring programme (LIM), follows the gathered using such methods will enable such questions to prescription-event monitoring methodology in that patients be answered. Pharmacogenetics could play a role in are identified on the basis of prescriptions. Eligible identifying individual risk factors for the occurrence of patients are identified in their pharmacies when they come and pick up for the first time the drug under study.
The role of the patient is gradually changing. From being Patients can register at the LIM website, and during a a person with little knowledge and little power, the present- certain period of time they will receive questionnaires day patient is highly informed about his disease and wants asking them about adverse events. The system is totally to participate actively in his treatment. As mentioned web-based; consequently, questionnaires can be sent via e- earlier, in some countries the importance of patients as a mail to participating patients at different points, allowing source of information about ADRs has been acknowledged.
the collection of longitudinal data. The high level of In these countries, patients have the option of reporting automation also allows a rapid collection and analysis of ADRs via the spontaneous reporting system. This patient empowerment will continue and, in the future, pharmaco- vigilance has to concentrate on this group as a source of 14. European Medicines Agency (EMEA) (2007) European Medicines information in addition to the more traditional groups, such Agency confirms positive benefit–risk balance for rosiglitazoneand pioglitazone. Available at The field of pharmacovigilance has made a tremendous 15. Information for healthcare professionals rosiglitazone maleate journey since it was recognised in the early 1960s after the (marketed as Avandia, Avandamet, and Avandaryl). Available at thalidomide disaster. Recent events, such as the withdrawal of aprotinin and the questioning of the safety of rosiglitazone, 16. Mangano DT, Tudor IC, Dietzel C (2006) The risk associated with show that it is a topic that lies close to people’s hearts. In the aprotinin in cardiac surgery. N Engl J Med 354:353–365 past few years there has been a major push in trying to change 17. European Medicines Agency (EMEA) (2007) European Medicines the existing pharmacovigilance systems in order to meet the Agency recommends suspension for marketing authorisation ofaprotinin-containing medicines for systemic use. Available at demands of the future. Scientific underpinning of pharmaco- vigilance is needed to ensure that it will develop as a scientific discipline and thereby contribute to the innovation needed in 18. Mitka M (2006) Report criticizes lack of FDA oversight. JAMA this field. The pharmacovigilance of tomorrow must be able to 19. Lenzer J (2004) FDA is incapable of protecting US “against identify new safety issues without delay. If we succeed herein, patient’s confidence in drugs will return. Furthermore, 20. Ray WA, Stein CM (2006) Reform of drug regulation—beyond an pharacovigilance methods must also be able to describe which independent drug-safety board. N Engl J Med 354:194–201 patients are at risk of developing an ADR and what the course 21. Furberg CD, Levin AA, Gross PA et al. (2006) The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med of the ADR is. One approach to doing this would be to use patients—more than has been done up to now—as a source of 22. Avorn J (2007) Paying for drug approvals—who’s using whom? information; this approach would be consistent with the growing patient involvement in drug safety.
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