Optimizing drug safety monitoring to enhance patient safety and achieve better health outcomes

Informations projet

MONITORING MEDICINES

N° de convention de subvention: 223566

Projet clôturé

Date de début 1 Septembre 2009

Date de fin 31 Juillet 2013

Financé au titre de

• Specific Programme "Cooperation": Health

Coût total € 2 236 129,80

Contribution de l’UE € 1 995 096,00

Coordonné par

Stiftelsen WHO Collaborating Centre for International Drug Monitoring
Sweden

Final Report Summary - MONITORING MEDICINES (Optimizing drug safety monitoring to enhance patient safety and achieve better health outcomes)

Executive Summary:

Pharmacovigilance actively, detect, assess, understand, and prevent adverse effects or any other medicine-related problem for safer patients. Monitoring Medicines project with the full title “Optimising drug safety monitoring to enhance patient safety and achieve better health outcomes” was set up in 2009, to learn more about the underlying reasons why adverse reactions to medicines occur and what more can be done to reduce patient deaths and negative health impact from undetected medicine safety problems globally. The consortium of 11 partners from Africa, Europe, and Asia carried out the project for nearly four years, September 2009 to July 2013.

The objective was to coordinate and encourage greater involvement of all stakeholders in a coherent effort to reduce medicine related patient harm and by influencing decision-making policies. Upon its completion in July 2013 this Coordination and Support Action project had achieved its anticipated results and beyond. Piloted activities and studies now develop into bigger research projects and best practice technology to enhance patient safety.

The project stimulated the participation of Small Medium Enterprise (SMEs), established relationships with European and global research schemes and is now disseminating best practices and knowledge across Europe and beyond. By bringing together partners from different parts of the world, coming with different skill sets from different backgrounds, opportunities for innovative solutions have emerged that might not otherwise have been explored.

The work was organised in four main layers:
• Supporting and empowering patients in reporting medicine-related problems
• Pharmacovigilance centres collecting problems related to medication errors
• Better use of existing global pharmacovigilance data
• Strengthening pharmacovigilance systems be developing additional methods
The project has made huge progress over the four years. Although the official end date of the project has passed, new developments and further research opportunities are still emerging from the project.
Key achievements:
• A WHO handbook for reporting of medicine-related problems from the general public was published.
• Practical tools for web-based reporting were developed with patient groups and regulatory authorities and implemented in countries
• Guiding principles for detection, analysis and prevention of medication errors for pharmacovigilance and patient safety centres were developed.
• Methods for identification of products of sub-standard quality from pharmacovigilance databases were developed
• Novel indicators for early identification of potential dependence liability from pharmacovigilance databases were developed and tested
• Comprehensive tools for assessment of patient risks related to HIV/AIDS medicines were developed and made available to the public
• New methods for safety monitoring of medicines introduced in Public Health Programmes were developed and field tested. Handbooks and data management tools were made available to investigators.
• Online tools for assessment of patient risks related to HIV medicines was developed

Project Context and Objectives:
Spontaneous reporting of suspected adverse drug reactions (ADRs) has remained the cornerstone of pharmacovigilance in Europe and in the world, particularly for identification of early signals of unknown medicine-related problems. The European pharmacovigilance system and the European pharmacovigilance database (EudraVigilance) have evolved to handle European regional pharmacovigilance and regulatory needs. Results from spontaneous reporting systems, although useful, do not provide all necessary facts and sufficient scientific rigour to support key evidence-based decision making. The European Union initiated the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), to further develop medicines safety collaboration and research, using methods other than spontaneous reporting.

At global level, WHO operates the Progrmme for International Drug Monitoring. The core of the Programme is an ADR database, VigiBase™, managed by WHO’s Collaborating Centre in Uppsala, (the Uppsala Monitoring Centre (UMC)). Spontaneous reporting systems are now established in 115 countries in all continents of the world, all of which forward reports to VigiBase.

Although existing pharmacovigilance systems are useful in identifying patient safety issues, there is considerable scope for optimizing and improving their use, particularly through wider inclusion of stakeholders in ADR reporting, promotion of harmonized reporting systems, and deeper analysis, dissemination and broader application of ADR data

The overall aim of Monitoring Medicines, was to enable learning about why adverse drug events occur so that we can act to reduce patient deaths and negative health impacts arising from undetected medicine safety problems globally.

Patient Empowerment

The project aimed to identify appropriate reporting methods and develop user-friendly reporting formats and tools, to facilitate and improve the quality of consumer reporting. The intention was to contribute to harmonized global reporting, which would allow accumulation of comparable data from consumer reports across regions, providing an additional perspective on medicine related harm other than that given by reporting from healthcare professionals.

Medication Error reporting

Studies of adverse events in developed countries have consistently shown that safety issues related to the use of medicines are one of the leading causes of preventable harm to patients. Capturing comprehensive data as a source of learning and the basis for preventive action is a cornerstone of improving patient safety. In promoting an extended role for national pharmacovigilance centres, Monitoring Medicines tried to demonstrate the value of and need for research, conducted across several countries, using agreed upon principles and criteria and aimed at deepening understanding of systematic failures responsible for the adverse incidents relating to drug prescribing, dispensing and administration. The project particularly focused on encouraging national pharmacovigilance centres to expand their activities to learn more from existing data through: collection of information on adverse events relating to prescribing, dispensing and administration, and international analysis of these data. This capacity has enabled one of the project partner Moroccan Poison and Pharmacovigilance Centre to work closely with the former National Patient Safety Agency now NHS Commissioning Board UK. This collaboration has influenced the Morocco PV centre to be the excellent and the leader dealing with Medication Error reporting in the region.
Broader and better use of existing pharmacovigilance data
Drug dependence liability

Evaluation of the dependence-producing properties of psychoactive substances uses laboratory studies and other methods. Pharmacovigilance was also included as a marginal provider of data based on rudimentary information from healthcare systems. A discussion organized by WHO among a number of the world’s leading pharmacovigilance experts and drug experts showed that no operational methods existed, although ideas on how to make better use of existing data had been proposed. Monitoring Medicines commissioned the UMC to develop state of the art data mining tools, enabling identification of complex combination of medicines versus terms that are predictive of dependence liability, thereby promoting a more evidence-based and less empirical method for selecting drugs for review by the WHO Expert Committee on Drug Dependence.

Substandard/Spurious/Falsely labelled/Falsified/Counterfeit medicines (SSFFC)

WHO data shows that all countries are affected by counterfeit or substandard medicines. Combating SSFFCs requires the coordinated effort of public and private stakeholders. The activities proposed by Monitoring Medicines intends to help determining whether there are specific reporting terms that are in fact surrogates of underlying quality issues in national pharmacovigilance data. An algorithm that systematically evaluates reports recording ‘decrease in therapeutic effect’ in VigiBase would be of value in identifying substandard and counterfeit products, the types of products susceptible to counterfeiting, and to an extent, delineating the origin and geographic distribution of the problem of counterfeiting.

Spontaneous reporting data enhanced through introduction of active and targeted spontaneous surveillance methodologies

Gaps in spontaneous reporting systems could be complemented with Cohort Event Monitoring (CEM), an ’active’ surveillance system modelled on an existing programme established in New Zealand. The CEM methodology can be adapted for use in any disease treatment programme and is particularly valuable for safety monitoring of new product introductions since it can:

• Provide the data for making evidence-based decisions on medicine selection
• Generate sound data in order to make an informed response to any medicine ‘scares’
• Minimize adverse effects that might affect patient safety and adherence by determining risk factors and means of risk prevention
• Facilitate early identification of ineffectiveness or treatment failure
• Identify medicine-medicine, medicine–disease or medicine–food interactions

The ambition of the Monitoring Medicines was to assist in the adaptation of the CEM methodology for use in Public Health Programmes by providing guidelines, capacity building and data management tools and by supporting field testing in selected countries.

Monitoring Medicines also wished to offer and field test a less resource demanding methodology than CEM for certain Public Health Programmes, particularly those in which a defined cohort of patients are returning to the same treatment centre for follow-up- Targeted Spontaneous Reporting (TSR, was chosen for the study of specific, identified risks with defined drug regimens in HIV/AIDS and TB.

Support for risk assessment for patients under HIV/AIDS treatment

Another objective of the project was to develop a user-friendly, web based query tool to enable health care workers to search and retrieve information contained in a database build by merging ADR data on HIV-medicines from several different sources. The ambition was to offer a risk score calculation tool, allowing evaluation of ADR development based on clinical data.

The project lead by Copenhagen HIV Programme created a pharmacovigilance database, using HIV ADR data, by merging HIV ADR from several sources into a common database storage of information of ADRs to ARVs (preferred terms, requiring medical education will be used). To develop information technology tools to easily search, retrieve and evaluate information from this database via a publicly available website and develop modules on website to test knowledge about such reactions.

Project Results:
Review of existing systems

A consultancy team led by Lareb Foundation, the Netherlands, was assigned to review current practices in countries with established systems for direct patient reporting of medicine related problems. A survey based on face-to-face or telephone interviews was carried out June – August 2010 and covered patient reporting systems in 11 countries in Europe (5), Asia (2), America (2) and Australia/New Zealand (2). In parallel with the survey an extensive review of the scientific literature was carried out. A draft review report, including a summary of the literature, was submitted to Monitoring Medicines in October 2010. It was shared for comments with other participants of the work package.
A review committee meeting, including representatives of several patient and consumer organizations, was organized in Uppsala, Sweden, in December 2010 to discuss the review report in detail. A report of the meeting, outlining the important discussions and conclusions, was produced and published on the project web site. The survey report formed the basis for a manuscript that was written for a scientific audience. This manuscript was accepted by a peer-reviewed journal and was published in 2012. The article also formed part of a PhD thesis written by the lead review team investigator Florence van Hunsel. Her thesis ‘The contribution of direct patient reporting to pharmacovigilance’ was published and successfully defended in November 2011.

Reference:
F. van Hunsel, L. Härmark, S. Pal, S. Olsson, K van Grootheest. Experiences with Adverse Reaction Reporting by patients – An 11 country survey. Drug Safety 2012; 35: 45 -

Handbook development

Two pharmacovigilance professionals from the Medical Products Agency, Sweden, and the Lareb foundation, the Netherlands, respectively were commissioned to write a first draft handbook on how to establish systems for consumer reporting of ADRs and other drug related problems. An expert group meeting was organized by WHO in Geneva at which the draft was discussed and recommendations for amendments made. Having considered also the results of the survey carried out, as mentioned above, the drafting team submitted a final version of the handbook in November 2010. The handbook was published by WHO in 2012 and was also translated into Spanish by the Spanish national pharmacovigilance centre. The handbook was distributed in the relevant language to the approximately 140 national pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring and posted on the web sites of WHO and UMC.

Reference: Safety monitoring of medicinal products: reporting system for the general public
www.who.int/medicines/areas/quality_safety/safety_efficacy/qas_safetymonitoringmp/en/index.html
Development of a general reporting system

At the meeting of the review committee mentioned above a technical expert team from Uppsala Monitoring Centre (UMC) presented a proposal for a general internet based solution for management of consumer reports, allowing submission of individual case safety reports (ICSRs) from anywhere to first a national pharmacovigilance centre and subsequently to international databases. The proposal included a mock version of a software user interface.

The committee nominated a small reference group, with representatives of consumer organizations and national pharmacovigilance centres, to work closely with the expert team in the final design of the reporting tool. Because of the imminent adoption of a new EU pharmacovigilance legislation, making consumer-reporting mandatory for all EU countries from July 2012, detailed work on the reporting tool was postponed until the second half of that year to ensure that the result would be fully compatible with EU regulations.

A web-based reporting system intended for the general public was developed by the UMC product management team. The software design was made in close collaboration with representatives of national medicines agencies and patient and consumer organizations. The needs, ideas and suggestions from the potential end users were taken into account in the design of the final product.

During the development of the main reporting tool one of the partners, Elliot Brown Ltd, undertook the development of a prototype interface that will facilitate the use of a standard adverse reaction terminology, in this case WHO-ART, in patient reporting of adverse reactions to pharmacovigilance centres.

The main elements of this project were:
• Re-ordering of WHO-ART terms under existing and new System Organ Classes (SOCs) to allow more intuitive searching for terms according to anatomical site.
• Development of electronic graphical representations of SOCs that might provide a simple means of searching for relevant adverse reaction terms.
• Development of a dictionary search tool incorporating the graphics and allowing interface with the national pharmacovigilance centre databases.

The resulting interface may be offered as an option to people reporting adverse reactions to pharmacovigilance centres in addition to their narrative descriptions of the reactions. The interface would be fully functional in its own right, but lessons learnt in its development could also act as a pilot and be relevant to any subsequent efforts to adapt also MedDRA, in addition to WHO-ART, for patient reporting. Before inclusion of the terminology prototype in the main reporting system some further work remains to be done, but this has not been prioritized for the piloting phase.

The resulting reporting system is built in such a way that any country accepting ICSR data in the standard ICH-E2b format can use it. Language, style sheets and logos can be adapted to meet local needs. The tool is directly compatible with UMC’s general ICSR data management system VigiFlow, used by approximately 60 countries world-wide. The patient reporting system can be used only in collaboration with a national pharmacovigilance centre. Countries (national pharmacovigilance centres) wishing to use this system, need to contact UMC to discuss the set-up. The information created will be transferred to the respective national centre for analysis and possible feedback to the patient. Information will be made available outside the national pharmacovigilance centre only when it so decides The standard system was developed only in English. Countries wishing to use it in another language need to take responsibility for translation of labels help texts etc. and write the necessary country specific caveats and manuals themselves. During the pilot testing of the system in 2012 it was translated into Croatian and Turkish. In Croatia and Turkey it is now operated in a live environment, integrated into the function of the web sites of the Croatian and Turkish drug regulatory authorities respectively.

The reporting system and tools for direct patient reporting was presented at the pharmacovigilance seminar at the 65th World Health Assembly in 2012. A more detailed presentation was made at the annual meeting of national centres participating in the WHO Programme for International Drug Monitoring in Brazil in November 2012 by representatives from UMC and the Croatian pharmacovigilance centre

Workshop on direct patient reporting

The consortium organized a workshop in the Netherlands 7 - 9 March, 2012 to discuss direct patient reporting. It was hosted by the Lareb pharmacovigilance centre. The workshop was attended by 30 representatives from national regulatory agencies and consumer/patient organizations from around Europe. All participants, from 10 European countries and Morocco, contributed actively in group work and discussions.

The following topics were discussed in the workshop:
• The need for pharmacovigilance and spontaneous reporting
• Experiences with direct patient reporting
• WHO handbook on setting up and running a reporting system for the general public
• The role of patient organizations in patient reporting
• The suggested patient reporting data management tool: flow of reports
• Provision of feed-back to patients and their organizations
• Benefits of working with patient organizations
• How to promote patient reporting globally
• Expected impact of the new EU legislation on pharmacovigilance
• Analysis of reports from spontaneous reporting: causality and signal assessment
• Dealing with negative attitudes against patient reporting

The participants also had hands-on experience with the new system by entering cases and by expressing their views on the functionality and user-friendliness of the tool.

The workshop participants agreed that, as a minimum, the reporter needs to know what will happen once the report is submitted. Some national centres do not have the manpower to contact all reporters individually. In this case it is important to let the patient know how (s)he can find out more and where to turn with questions. Meeting the expectations of patients and consumers is critical.

It became apparent during the workshop that patient/consumer organizations and regulatory authorities have a joint interest in optimizing the safety of patients needing medicines to prevent, cure, control diseases or alleviate symptoms. Sharing information and perspectives between the parties is for the ultimate benefit of patients.

Reference:

Plöen M. Workshop on direct patient reporting. Uppsala Reports 2012; 57: 10 - 11

Patient reporting at World Health Assembly

Monitoring Medicines managed to host a lunch seminar at the 65th World Health Assembly (WHA) in May 2012, focusing on ‘Empowering Patients in Pharmacovigilance’. The seminar, attended by approximately 90 WHO delegates, media representatives and other interested parties, was chaired by Mr Kees de Joncheere, Director of WHO Essential Medicines and Pharmaceutical Policies department. Presentations were made by four of the consortium partners and three representatives of patient organizations from Europe and Africa. A lively session of questions and answers followed. It was finally stated that if we do not count on patients, patient-care will not count.

Reference:
Lindroos H. Patient reporting at WHA. Uppsala Reports 2012 58:18

Pal S., Olsson S. Capturing patients' experience of the harms of medicines
www.who-umc.org/DynPage.aspx?id=105196&mn1=7349&newsid=10874

Objective 2 (work package 5 – 6)

Training workshop on determining preventability of harm

The Pharmacovigilance Centre in Morocco identified, by circulating a questionnaire to pharmacovigilance centres participating in the WHO International Drug Monitoring Programme, 10 national pharmacovigilance centres with an interest and capacity to participate in a development project for expanding the scope of activities of these centres, to identify medication errors. In particular, the questionnaire sought to identify centres with some prior experience in handling reports of medication errors.

A training workshop for the 10 national pharmacovigilance centres (Morocco, Kenya, Iran, New Zealand, Thailand, Spain, Switzerland, Nigeria, Brazil and Tunisia) was organized in Rabat, Morocco in March 2011. Prior to the workshop the centres had been asked to submit individual case safety reports related to a few pre-defined medications

The focus of the training was on identifying, analyzing, and preventing medication errors, aiming to encourage national pharmacovigilance centres to expand their activities and to learn more from existing data through:

• Hands-on exercises in order to improve reporting of medication errors and, most importantly, to learn about various methods to assess preventability of adverse drug reactions. The Moroccan centre had developed an assessment method/tool intended to help identify medication errors that are otherwise flagged as ADR reports in national PV databases (the p-method). The p-method is a tool to determine whether the ADR is preventable and in fact due to a medication error. The p-method was tested on 80 of the ADR reports submitted by the 10 centres.
• Increasing the capacity of national pharmacovigilance centres to analyze reports of medication errors.
• Increasing the capacity of national centres to take action to change the behaviour of health care providers in order to minimize the recurrence of medication errors
Contributions from patient safety centres, represented by the National Patient Safety Agency, UK and the Institute for Safe Medication Practices, Canada, enriched the training to include different approaches to classification and terminologies related to medication errors, root cause analysis and failure mode and effect analysis.

It was realized that pharmacovigilance and patient safety centres receive medical incident reports of different nature and have to operate in slightly different ways but, in the interest of patient safety they need to collaborate, share information and learn from each other. There is scope for the international networks of pharmacovigilance and patient safety centres to align their activities.

Following on from the training, participants were invited to assess preventability of a fixed set of ICSRs, using the approaches learned at the workshop. Consistency of assessments was analyzed. Results, conclusions and recommendations were used for a scientific paper on preventable medication errors that was later submitted to a peer-reviewed scientific journal for possible publication. The methodology used during the workshop was also applied by a working group at the annual meeting of national pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring in Dubrovnik, Croatia 2011.

Reference:
Nilsson E. Medication Error Training in Rabat. Uppsala Reports 2011; 53:16

Detecting, analyzing and preventing medication errors within pharmacovigilance centres

With the aim of increasing the capacity of pharmacovigilance centres in identifying and understanding the root causes of preventable ADRs WHO, UMC, the UK National Patient Safety Agency (NPSA) and the Morocco pharmacovigilance centre joined forces in developing a handbook on medication error management. A draft publication; ‘Reporting and learning systems for medication errors: detecting, analyzing and preventing within pharmacovigilance centres,’ was prepared. This document is intended to strengthen the capacity of national pharmacovigilance centres to identify, analyse and issue guidance to prevent or minimise medication errors that harm patients. In addition it is intended to stimulate co-operation between national pharmacovigilance centres and patient safety organizations to work together to minimize preventable harms from medicines.

Background and technical guidance is provided in the document on the principles and methods of medication error incident reporting and learning. This information is intended to assist pharmacovigilance and patient safety organizations to begin to use the same philosophy, terminology and processes in undertaking this work.

The draft was sent out to stakeholders in the second half of 2012 and comments were taken into consideration for the final document that is scheduled to be printed as a WHO handbook in December 2013. It is expected to be used extensively by national pharmacovigilance and patient safety centres around the world. The general content of the guidance document was presented at the annual meeting of national pharmacovigilance centres taking part in the WHO Programme for International Drug Monitoring in Brazil, November 2012.

Objective 3 (Work package 7 – 8)

Defining early indicators of drug dependence liability

The UMC research department developed a novel approach for identification of drug dependence relatedness.The basis for deriving novel indicators of dependence and dependence relatedness was the identification of all ADR terms whose reporting was associated with the reporting of the term ‘Drug dependence’, within each of three different subsets of the global WHO ICSR database, VigiBase. These three subsets corresponded to three different pharmacological categories – ‘benzodiazepines’, ‘opioids’ and ‘others’ - within the reference set of medicines. The ADR terms thus identified were classified into (i) terms directly relating to issues of dependence or dependence relatedness; (ii) terms describing cognitive and mental effects; and (iii) terms describing physical effects.

The primary indicators were then defined as co-reporting of either (A) one term from (i) and one from (ii) on the same report; or (B) one term from (i) and one from (iii) on the same report. The results suggest that while the derived indicators are not universally superior, they possess useful properties, in particular for a large database such as VigiBase. They are generally very specific, meaning that when they flag for potential dependence or dependence relatedness, this is likely to be correct. On the other hand, they will generally highlight rather few potential issues, and will therefore not find everything. However, in some cases they will also allow for an earlier detection of a problem. These properties imply that these indicators are very suitable to use as add-ons to other indicators: they will hardly increase the workload in terms of highlighting many more potential issues, but they will allow for earlier detection of some issues, and also for detection of issues otherwise completely missed.

The full report of the development team is published on the Monitoring Medicines web site. A description of the new method was submitted to and accepted for an oral presentation at the 26th International Conference on Pharmacoepidemiology and Therapeutic Risk Management in August, 2010. The UMC research team applied the newly developed approach to the contentious topical subject of the dependence producing potential of pregabalin. In a letter published in the European Journal of Clinical Pharmacology in March 2011 it was shown that an earlier detection of the dependence producing properties of this medicine might have been possible had the new method been available.

Reference:

Caster O., Edwards I.R Norén N., Lindquist M. Earlier discovery of pregabalin’s dependence potential might have been possible. Eur J Clin Pharmacol 2011; 67(3):319-20

Identifying clusters indicating presence of substandard of falsified medicines

The UMC research team identified all terms in the MedDRA terminology that can be associated with effects of inferior quality products. A data mining approach was then developed to identify medicinal products that were:
- Associated with a higher than expected number of ICSRs in VigiBase compared to other products in the same country containing the same substance
- Excess of reports on the selected terms during one year in a specific country
- Cases strongly indicating falsified medicines by a set of chosen preferred terms or by additional text on the reports

A random sample of such clusters of excess reporting and the top-30-results of the threefold method were further investigated for confirmation of clinical accuracy by searching information from the web sites of the regulators of the respective countries or by contacting the national pharmacovigilance centres. In several instances, the clusters identified in the database indicating effects of substandard or falsified medicines were confirmed by independent information of batch withdrawals or regulatory confirmation of product quality problems. An independent questionnaire survey was also carried out to find out to what extent national pharmacovigilance centres deliberately submit or withhold ICSRs on quality issues from VigiBase.

A description of the method used for identification of suspected substandard medicines in VigiBase was presented at the 27th International Conference on Pharmacoepidemiology and Therapeutic Risk Management 2011. It has also been shared with the project manager for SSFFC at WHO and representatives of the EDQM, Medicrime project at the Council of Europe. Validation of the suitability of the data mining method for routine use requires resources and the involvement of drug enforcement and pharmacovigilance centres in countries contributing ICSRs to VigiBase. Such a project is expected to be carried out with external funding late 2013 – early 2014.

Objective 4 (work package 9 – 13)

Defining preferred pharmacovigilance methods to supplement spontaneous reporting

An expert group meeting was organized by WHO in Geneva in April 2010 to discuss active and stimulated passive surveillance methods. Meeting attendees included representatives of three of the Monitoring Medicines project partners, an epidemiologist from New Zealand, one HIV specialist and one TB specialist from WHO. The group discussed various pharmacovigilance methods. There was general consensus to replace the term ‘stimulated passive reporting’ with ‘targeted spontaneous reporting’, to best serve the needs of programmes such as HIV and TB. The group identified the following two methods:

1. An active surveillance method that would leverage TB treatment as a use case; the principles of the Intensive Medicines Monitoring Programme in New Zealand would be adapted for the active monitoring of patients receiving TB medicines as part of a public health programme.
2. Targeted spontaneous reporting: an adaptation of the spontaneous reporting method, that would define the principles for
- monitoring the safety of medicines given to specific target populations (eg, HIV or TB treatment cohorts)
- introducing pharmacovigilance as a best practice that improves the standard of care of patients receiving any treatment, particularly long-term treatment. Patients are to be asked about ADRs at every regular encounter
- the option of focusing attention on suspected reactions of particular concern to the chosen therapy

Dr Coulter, an expert from New Zealand, was assigned the task of developing the above principles into a practical Handbook for the safety monitoring of TB medicines.

A practical handbook on the Pharmacovigilance of medicines used in the treatment of tuberculosis
The handbook is a very detailed manual, giving a step by step approach to undertaking the pharmacovigilance of anti-tubercular medicines. It is intended to be a source of practical advice for pharmacovigilance centres and health professionals involved in the National TB Control Programmes, and it is already in use by WHO TB experts.
The handbook describes three main methods for safety monitoring of anti-TB medicines: spontaneous reporting, Cohort Event Monitoring and Targeted Spontaneous Reporting. The draft handbook was reviewed by pharmacovigilance and disease experts before final editing and printing. The handbook has been widely distributed within the WHO TB programme and promoted to national pharmacovigilance centres. It is available for free from the WHO web site. The principles of spontaneous reporting, Cohort Event Monitoring and Targeted Spontaneous Reporting were described in a separate scientific article that has been published in a peer-reviewed journal.

References:
A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis – Enhancing the safety of the TB patient
http://www.who.int/medicines/publications/pharmacovigilance_tb/en/index.html

Pal S., Duncombe C., Falzon D., Olsson S. WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems. Drug Safety 2013; 36:75 – 81

Training workshops in pharmacovigilance methods that complement spontaneous reporting

To develop additional pharmacovigilance methods to complement data from spontaneous reporting systems, two training courses were organized in Mombasa, Kenya in June 2011: one course on Cohort Event Monitoring (CEM) of anti-malarial medicines, and one on targeted spontaneous reporting (TSR) in HIV treatment programmes. In Kiev, Ukraine a similar course was held in November 2011 on CEM of Anti-retroviral medicines.

CEM and TSR in Kenya

The Pharmacy and Poisons Board (PPB), Kenya, hosted and organized these two courses with participants from Kenya, Burkina Faso, Botswana, Zimbabwe, Ethiopia and Uganda. Speakers included experts from the Kenyan National Pharmacovigilance Centre, WHO, UMC, the WHO Collaborating Centre for Advocacy and Training in Pharmacovigilance in Accra, Ghana, the Copenhagen HIV Programme, representatives from the Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya and others.

The two courses were held in parallel. Participants from Zimbabwe, Uganda and Botswana, teamed up to learn about the TSR method whilst participants from Kenya, Ethiopia and Burkina Faso gathered in to study the CEM method.

CEM in Ukraine

A third training workshop focusing on Cohort Event Monitoring of ARVs was held in Kiev, Ukraine 21 – 25 November 2011. Representatives of pharmacovigilance and HIV/AIDS programmes in Belarus, Moldova and Ukraine attended the training.

Trainers included experts from Swissmedic, Switzerland, WHO, WHO Collaborating Centre for Advocacy and Training in Pharmacovigilance in Accra, Ghana and UMC. An overview of treatment options in HIV/AIDS and common and important patient risk scenarios were provided by an expert from the HIV-Programme of Copenhagen University. Training on the specifics of the Cohort Event Monitoring methodology and the CemFlow record management system was provided by Geraldine Hill, University of Dunedin, New Zealand, Henry Irunde, TFDA, Tanzania, Comfort Suku, NAFDAC, Nigeria and Magnus Wallberg, UMC. Steve Corquaye, an HIV patient counselor from Accra, Ghana, shared his knowledge of patient perceptions of medication related risks and how to manage them.
Lectures were carried out using simultaneous translation between English and Russian.

Reference

Nilsson E., Ako-Adounvo S. Complementing existing pharmacovigilance methods Uppsala Reports 2011; 54: 16
Olsson S. CEM training in Ukraine. Uppsala Reports 2012; 56:9

Selecting countries for pilot implementation of priority methods

Participants from the respective courses were given the opportunity to develop and submit a project proposal to the WHO. Three of the proposals (two in CEM and one TSR) were then selected for financial support from the Monitoring Medicines project funds, to pilot the adaptation and implementation of CEM and TSR, in malaria and HIV programmes respectively.
• Uganda was selected as the implementation country for the TSR method to monitor patients on certain anti-retroviral medicines.
• Kenya was chosen to initiate CEM of anti-malaria medicines.
• Belarus was the selected country to pilot CEM of anti-retroviral treatment.

These three countries collected reports of adverse events or suspected adverse reactions in patients treated with medicines for malaria or HIV/AIDS, using CEM and TSR methods.

Pilot implementation

Uganda started implementing the programme to monitor patients on antiretroviral therapy (ART) using the TSR method. The project was formally launched in May 2012 in the presence of representatives of Ministry of Health, the National AIDS Control Programme of Uganda and of the lead participant of the Monitoring Medicines project. The project representative also visited some of the data collections sites on the occasion.

An interim report of activities May – December 2012 was presented by the Uganda management team in February 2013 and a final report in July 2013

Kenya started initiating Cohort Event Monitoring (CEM) in August 2012, aimed at identifying safety problems in patients faced with recently-introduced artemisinin combination therapy for malaria.

Belarus launched the data collection phase of its pilot CEM project of anti-retroviral therapy in the country in January 2013 at five active HIV/AIDS treatment centres.

Pilot project surveys

The management team of the Uganda TSR project presented the approach chosen and the interim results achieved at a meeting of international pharmacovigilance experts in Zimbabwe in August 2012. The presentation stimulated a lively discussion and suggestions for analysis and interpretation of the results were provided by the group.

An expert team representing WHO and the UMC visited Kenya to survey progress of the CEM project of anti-malaria medicines in February 2013.The experts visited data collection sites and held discussions with representatives of the National Malaria Control Programme and the Kenyan Pharmacy and Poisons Board. A survey report from the team was submitted to the management of the Monitoring Medicines project.

Another team of experts from WHO and UMC visited Belarus in February 2013. In addition to making visits to three clinics taking part in the data collection for the CEM programme, they also held discussions with representatives of Ministry of Health and the national pharmacovigilance centre.

References:

Lindroos H. Experiences from CEM in Kenya. Uppsala Reports 2013; 61:12
Hill G. Monitoring Medicines in Belarus. Uppsala Reports 2013; 61: 12 – 13

Pilot projects results

Belarus

At the time of closure of the Monitoring Medicines project the pilot implementation of the CEM programme for antiretroviral treatment of HIV patients in Belarus had reached about 50% of its projected enrolment of 800 patients from all five sentinel sites. Compliance with treatment was satisfactory and loss to follow-up was restricted to about 11%. About 36% of exposed patients had experienced adverse reactions, most of them at expected frequencies. Serious but expected reactions happened to almost 5% of patients but no serious, unexpected reactions. Managers of the Programme were satisfied with the electronic tool for data management, CemFlow and the networking and communication opportunities created by the CEM-activity.

Uganda

The pilot project in Uganda focused on renal toxicity in a defined population of HIV infected clients on tenofovir-based regimen and mothers in the Prevention of Mother-to-Child Therapy programme in two treatment sites. Targeted Spontaneous Reporting (TSR) was utilized.
During the one-year pilot 0.19% of the 10 000 exposed to tenofovir-based treatment were reported with renal toxicity. Reporting rates increased exponentially as compared with normal spontaneous reporting. Awareness among HIV/AIDS programme managers of the need to follow up medication safety was considerably improved as were relationships between the pharmacovigilance centre of the regulatory authority and the Public Health Programme. Project managers in Uganda recommend a wider roll-out of the TSR methodology in the country.

Kenya

A CEM programme monitoring the safety of artemether-lumefantrine in malaria treatment was carried out in 8 sites between July/August 2012 and June 2013. In total 3347 patients were enrolled of which 3.3% were lost to follow-up. Data on recorded events is still being analyzed

Sex and age distribution of patients enrolled in the CEM-programme in Kenya

Development and adaptation of a data management tool for CEM

CemFlow® is a data management tool developed and maintained by the UMC. The tool is built to assist in collecting and managing data from CEM programmes. CemFlow is web based and hosted by the UMC in Uppsala, Sweden.

The core of CemFlow is the Data Entry module where the recording of patient related data occurs and the Search and Statistics module where the analysis of the collected data is performed. CemFlow is strictly patient based since a record is kept for every patient entered into the CEM programme, whether (s)he will experience an adverse event or not. Data collection is based on patient visits and starts with an initiation visit. Patient’s details such as name, address, age, sex, past medical history etc are recorded. The patient should receive a CEM ID number which should be recorded and kept through all follow-up visits. The patient’s medication is recorded - not only the monitored drugs, but all medicines taken by the patient should be entered. Specific laboratory tests that may be needed can also be entered. The baseline data of diseases, events and concomitant drugs are important for the analysis.

Within the Monitoring Medicines project, adaptation of CemFlow was developed for collection of information on antiretroviral medicines (ARVs) used in HIV/AIDS, and also techniques allowing partially off-line data entry. The upgrade to a tool allowing off-line data entry made a very significant difference to the suitability of the software in countries with limited access to broad-band internet, e.g. in Africa. The software is currently being used by pharmacovigilance programmes in Belarus, Tanzania, Kenya, Zimbabwe, Ghana and Nigeria.

Reference:

www.who-umc.org/DynPage.aspx?id=98102&mn1=7347&mn2=7252&mn3=7254&mn4=7337

Establishing a HIV pharmacovigilance database

The Copenhagen HIV Programme produced a website with the purpose to:
• Create a database storage of information of ADRs to ARVs based on published literature
• Develop information technology tools to easily search, retrieve and evaluate information from this database via a publicly-available website
• Develop modules on website to test knowledge about such reactions

The website was developed to allow for both medical staff as well as non-medical staff to seek knowledge about ADRs related to ARVs. The website presents evidence-based knowledge with up to date research from PubMed. It allows for searches across the site and PubMed, access to online training material and accompanying tests to evaluate the learning objectives. Available online training material was developed for the advanced e-learning course on “HIV-related diseases, treatment and care”. The full course is covering many other areas than just ADRs. To keep the content focused on ADRs, the relevant modules have been extracted for the website. The website currently contains five different tools to asses risk of ADRs related to ARVs. All of these have been tested and are based on algorithms published in peer-reviewed journals. Explanation and citation reference for each of these is given on the website.

The content of the website is kept updated through linkage with general training activity at Copenhagen HIV Programme through re-use of material developed for online training courses such as the “HIV-related diseases, treatment and care” held by CHIP during spring 2012 at the University of Copenhagen.

CHIP has also devised a patient management module for the website that allows the risk assessment tools to be connected and allow for physicians to use the tool to track the development of various risks over time for their patients. The system allows for physicians to create an account, enter and anonymize data on their patients, calculate risks and plot this on a chart that shows the change in risk over time. The risk assessment tools are already used by some physicians as part of their patient care.

The web site is connected to the HIV section of the WHO Pharmacovigilance Toolkit (www.pvtoolkit.org). It has also been presented at a pharmacovigilance seminar at the 65th World Health Assembly in May 2012 (see above).

Reference:
www.hivpv.org

Potential Impact:
Reporting of medicine related problems directly from the general public

Modern pharmacovigilance, or adverse drug reaction monitoring as it was known at the time, was initiated in the 1960s. There was then a strong belief that reporting had to be reserved for professionals with a formal training in making a distinction between symptoms of disease and symptoms caused by a medicine used to treat that disease. Consequently adverse reaction reporting was, in most countries, made into an exclusive responsibility for physicians and dentists. It was felt that observations from lay persons would create random noise that would disturb reporting patterns that professionals in signal analysis are looking for. It was also perceived that the general public would not know which data elements in a case report are of critical importance for causality assessment and reports from the public would be of low quality or unsuitable for decision making.

As pharmacists made their way into hospital settings in many countries and clinical pharmacy became a speciality, it was realised that pharmacists and also nurses could make valuable and unique contributions to the body of evidence on medicine related problems. Patient and consumer right advocates started demanding that their concerns also be considered and be taken seriously. A few analyses from countries accepting spontaneous reports of suspected adverse reactions from any source started to indicate that reports from the general public contributed favourably to the general knowledge base on medicine related harm. It also provided fast track reporting and a perspective not represented by reporting from professionals.

To be accepted by the pharmacovigilance professional community and regulatory decision makers the added public health value of direct reporting from the public of suspected adverse drug reactions had to be supported by scientific evidence. Such evidence started to emerge in the early years of the 21st century. It contributed, together with demands for empowerment from consumer and patient organizations, to the inclusion of mandatory patient reporting in the new EU pharmacovigilance legislation coming into force in July 2012.
Monitoring Medicines has made major contributions to the acceptance of direct patient reporting as best practice in pharmacovigilance. The approach was systematic and rigorous starting with an in-depth interview analysis of practices used in pharmacovigilance centres in 11 countries in different parts of the world with established systems for direct patient reporting. This study was published in Drug Safety, one of the main peer-reviewed scientific journals read by pharmacovigilance professionals. The chief investigator, Florence van Hunsel, also incorporated the analysis as a chapter in her PhD thesis with the title ‘The Contribution of direct patient reporting to pharmacovigilance’ successfully defended in November 2011. With this process the scientific rigor of the review and the added value of direct patient reporting as a whole to pharmacovigilance were firmly established.

To advocate the acceptance of direct patient reporting among pharmacovigilance centres and professionals globally, the World Health Organization, one of the Monitoring Medicines beneficiaries, initiated the development of a handbook on reporting systems for the general public. The development process involved pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring, and the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP). Once ready in its original language, English, it was translated into Spanish by the national pharmacovigilance centre in Spain. The appropriate language versions were then disseminated to all pharmacovigilance centres in the WHO network and made available for downloading from the web sites of WHO and UMC. The handbook is also accessible from the WHO pharmacovigilance toolkit.

The next step in facilitating the practical establishment of reporting systems for the public was to devise a general facility suitable for submission of reports and management of data in a manner adapted for analysis at national pharmacovigilance centres. Through an iterative process the UMC developed such a tool in close collaboration with Monitoring Medicines partners, representatives of several European regulatory authorities and consumer organizations. The tool can be used by any country accepting adverse reaction reports in the standard E2b format. Language, style sheets and logos can be adapted to meet local needs. The facility will always be connected to a national pharmacovigilance centre and reports will be transmitted to the WHO database, VigiBase, according to the same reporting routines as for all other case reports. During the pilot implementation phase Croatia and Turkey decided to adopt the system, now integrated into the function of the web sites of the Croatian and Turkish drug regulatory authorities respectively.

To ensure that the approaches and systems developed by the consortium would have the acceptance and buy-in from the key stakeholders, patient/consumers and national pharmacovigilance centres, a three-day workshop was organized in the Netherlands with 30 representatives of 10 European countries and Morocco in March 2012. The patient reporting handbook was discussed and hands-on sessions on the web based reporting facility were organized, adding to a final adjustment of the prototype.

The consortium formally advised the EMA of the availability of the reporting tool in connection with the public consultation on European Good Pharmacovigilance Practice in April 2012. Representatives of pharmacovigilance centres participating in the annual meeting of the WHO Programme for International Drug Monitoring in Brasilia, November 2012, were given a presentation of the facility for patient reporting available to all countries and how it is implemented in Croatia.

In an attempt to influence the highest decision makers in healthcare in countries on a global scale, Monitoring Medicines managed to organize a lunch seminar at the 65th World Health Assembly in May 2012, focusing on ‘Empowering Patients in Pharmacovigilance’. The seminar, attended by approximately 90 WHO delegates, media representatives and other interested parties, was chaired by Mr Kees de Joncheere, Director of WHO Essential Medicines and Pharmaceutical Policies department. Presentations were by four of the consortium partners and three representatives of patient organizations from Europe and Africa. A lively session of questions and answers followed. It was finally stated that if we do not count on patients, patient-care will not count.

Activities of the Monitoring Medicines consortium attracted attention of the PROSPER consortium (Patient-Reported Outcome Measures in Safety Event Reporting) supported by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Monitoring Medicines provided factual information and comments for the report of the PROSPER consortium to ENCePP.

In summary, the Monitoring Medicines project has investigated current patient reporting practices in countries and subjected those practices to critical review by domain experts. Expert recommendations have been included in the development of general guidelines for the establishment of patient reporting systems in countries. Web-based reporting tools adapted to the specific needs of patients have been developed, field tested and made available for general use. Advocacy for direct patient reporting has also been carried out, most significantly at the World Health Assembly

Objective 2 (work package 5 – 6)

Detecting, analyzing and preventing medication errors

Legislators and regulators have given a lot of attention to medicine safety over the last 15 – 20 years. Considerable methodological progress has also been made in pharmacovigilance. Regulations have been introduced that have forced both national regulatory authorities and marketing authorization holders to engage in pharmacovigilance. Major investments have been made to create harmonized systems for reporting, data management and sharing of information between companies and regulators.

Patients seem to be the last to benefit from the attention and investments made in medicine safety. Studies of drug-related diseases in healthcare show that the burden of such problems is of the same or greater magnitude today as it was some 20 years ago. Approximately half the medicine-related problems leading to hospitalization are still considered preventable, i.e. due to medication errors. Patients are no safer today when taking medicines than they were 20 years ago. Organizations responsible for healthcare and health insurance systems continue to overlook the lives lost, the considerable suffering and the cost of treating medicine-related diseases, even though it is clear that a lot could be saved by using medicines according to recommended practices and latest evidence.

Traditionally pharmacovigilance centres have focused on harm caused by the inherent properties of medicines and their interactions with patients and their conditions. Preliminary studies have shown, however, that a large proportion of reports submitted to pharmacovigilance centres relate to preventable harm i.e. caused by medicines being used inappropriately, not according to recommended practices and latest evidence. Pharmacovigilance centres can thus be important for the early detection and analysis of medication errors and for the process leading to prevention of further patient harm.

Some countries have established centres specifically focusing on safe medication practices in healthcare. The activities of these patient safety organizations may include the collection and analysis of medication error reports, root cause analysis, developing and promoting prevention strategies and dissemination of information leading to improvement of patient safety and a decrease in medication errors.

The Monitoring Medicines project strengthened patient safety efforts globally by combining the experience, competence and data resources of both pharmacovigilance and patient safety organizations. The two networks that in the past have used different definitions, terminologies and work processes, were brought together in an effort to combine their strengths.

In the first phase a joint training activity was organized in Rabat, Morocco, in 2011 with participation of representatives of 10 pharmacovigilance and patient safety centres from 5 continents. The faculty was recruited from both pharmacovigilance and patient safety organizations. Definitions and working methods were compared in an attempt to attain common understanding and harmonization. Tools for analysis of preventability and preliminary root cause analysis in adverse reaction reports were tested.

Experiences from the Rabat workshop were brought to a working group session on medication errors conducted at the 34th Annual Meeting of WHO Programme for International Drug Monitoring in Dubrovnik, Croatia, in November 2011. The working group session was summarized in the WHO Pharmaceuticals Newsletter 2012 No 1 p 25 www.who.int/medicines/publications/Newsletter_1_2012.pdf

A process was initiated to develop a WHO manual on medication errors to strengthen the capacity of pharmacovigilance centres to identify, analyze and issue guidance to prevent and minimize medication errors. It is intended also to stimulate cooperation between pharmacovigilance and patient safety organizations to work together to minimize preventable harm from medicines. The WHO handbook ‘Reporting and learning systems for medication errors: detecting, analyzing and preventing within pharmacovigilance centres,’ is expected to be published in December 2013.

The essential message of the manual was presented at 35h Annual Meeting of WHO Programme for International Drug Monitoring in Brasilia, Brazil, in November 2012

The manual will be circulated to all national pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring and to patient safety centres in the International Medication Safety Network. It will also be available for downloading from the web sites of WHO and UMC and be accessible from the WHO pharmacovigilance toolkit www.pvtoolkit.org

The Monitoring Medicines project has given attention to medication errors as a responsibility for pharmacovigilance centres. As a result the subject is now a regular part of the curriculum of the UMC annual pharmacovigilance training course. Two video recorded lectures on the subject are available from the UMC web site. http://media.medfarm.uu.se/play/kanal/4

A representative of Monitoring Medicines was a speaker at a workshop on Medication Errors at the European Medicines Agency 28 February – 1 March 2013.

Monitoring Medicines has interacted with representatives of the WHO Patient Safety department to introduce the collaboration between pharmacovigilance and patient safety networks and to express an interest in coordinating effort should the WHO Patient Safety department start focusing on medication errors. Recent initiatives from the Department indicate that attention will be given to medication errors in the immediate future. The WHO team for Medicine Safety and Pharmacovigilance (SAV) is being involved in these initiatives.

Objective 3 (Work package 7 – 8)

Drug Dependence and Substandard Medicines

Both national and international databases of individual case safety reports, established with the intention of monitoring harm associated with medical treatment have primarily been used to screen for the most common adverse reactions explained by the pharmacology of the medicine or the hypersensitivity or vulnerability of the patient. In spite of the large volume of reports collected in modern databases, problems associated e.g. with drug abuse or dependence have not been effectively identified. Also patient effects of poor quality medicines have escaped identification because the analytical methods have not been optimized to unravel their characteristic features from the bulk of the data.

As a consequence of the publication in 2002 of the WHO definition of pharmacovigilance as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse drug effects or any other possible drug related problems’, a wider spectrum of drug related patient harm were reported to and collected in pharmacovigilance databases. The last 15 – 20 years pharmacovigilance systems have also been established in many low- and middle-income countries (LMIC) in which problems of inferior drug quality and falsifications are common challenges to public health. To be relevant for patient safety, pharmacovigilance systems need to develop methods to identify signals indicating possible presence of substandard of falsified medicines on the pharmaceutical market.

Monitoring Medicines commissioned the UMC team for methodological research to develop methods for screening of the WHO database, VigiBase, to improve the chances of finding early indications of drug abuse or dependence potential of medicines and clusters indicating the presence of substandard or falsified medicines in a particular drug market.

Drug dependence

The UMC team identified a set of indicators for dependence relatedness based on a retrospective analysis of VigiBase. The indicators were based on
• Terms directly relating to issues of dependence
• Terms describing cognitive and mental effects that could, indirectly, relate to issues of dependence
• Terms describing physical effects that could, indirectly, relate to issues of dependence
A computational model using disproportionality analysis of reporting in VigiBase was then developed. It was shown in experiments that the new analytical method would have a higher predictive specificity in identifying issues of dependence liability than previous approaches. Advice on how to adapt the methodology to other, smaller, datasets are given. The results also demonstrate that ICSRs are a useful resource for the identification of potential liability of drug dependence. The full study report is available from the Monitoring Medicines web site www.monitoringmedicines.org/graphics/27504.pdf

The methodology was presented at the 26th ICPE: International Conference on Pharmacoepidemiology & Therapeutic Risk Management in Brighton, UK, in August 2010

The newly developed methodology was applied to the practical example of pregabalin, the dependence potential of which was discussed in the scientific media at the time. In a letter to the European Journal of Clinical Pharmacology (Eur J Clin Pharmacol 2011; 67(3):319-20) the authors claim that the methodology developed by the UMC for Monitoring Medicines would have allowed the dependence potential of pregabalin to be detected in VigiBase about 3 years earlier than would have been the case with the previous routine assessment method. The new analysis approach is currently being introduced as a routine method in the signal analysis triage used at the UMC.

Since the opportunities for identification of dependence and abuse potential of new medicines are limited during well controlled clinical trial conditions it is of great importance for public health to have sensitive yet reliable methods available for analysis of clinical information from early stage routine medicine use post-marketing. The Monitoring Medicines project has contributed to optimizing such methods for use in the global ICSR database. Putting these improved methods into routine use should offer better opportunities for providing future earlier warnings of a risk for dependence and abuse that often remain undetected.

Identifying clusters of possible sub-standard or falsified medicines

The global circulation of sub-standard and falsified medicines is currently considered one of the major medicine-related threats to public health, particularly in LMIC where the availability of such products is the highest. All possible approaches to assist in the identification of sub-standard products in the pharmaceutical market in countries should be employed to enable regulatory and other preventive measures to be taken. Analyses of ICSR databases have so far not been used to provide signals regarding the circulation of medicinal products of substandard quality.
The methodology developed on behalf of Monitoring Medicines is unique. It focuses on instances where reporters have observed an unexpected lack of effect or other sign indicative of a quality problem. The methodology uses an analysis of disproportionality in the reporting of such problems relating to a particular medical product, reported from a specific country during a limited time period (1 year). A screening of the WHO ICSR database, VigiBase, highlighted more than 4000 products with an excess reporting of suspected quality inadequacies. A limited effort to verify a random sample of the highlighted clusters could confirm that some of them indeed were related to product problems in the country of origin. Further validation of the method needs to take place, involving pharmacovigilance centres and enforcement agencies in countries, before it can be taken into routine use as a reliable tracking mechanism for sub-standard and falsified medicines in countries. Already at the present stage it can be established that ICSR databases can be a valid source for information on the existence of suspected substandard medicines in the pharmaceutical market, provided reporters are encouraged to submit reports on unexpected lack of effect and other quality problems to pharmacovigilance centres.

The methodology and the development process are presented in full on the Monitoring Medicines web site www.monitoringmedicines.org/graphics/27523.pdf. It was presented at the annual meeting of representatives of national centres participating in the WHO Programme for International Drug Monitoring in Brasilia, November 2012

Discussions are currently taking place between UMC and WHO on the process for validation of the methodology and the mechanism for informing the WHO SSFFC project through routine monitoring of VigiBase. A validation of the data mining method for routine use involving drug enforcement and pharmacovigilance centres in countries contributing ICSRs to VigiBase is expected to be carried out with external funding late 2013 – early 2014. The Monitoring Medicines approach to analysis of ICSR databases for identification of sub-standard medicines has also been shared with the Council of Europe EDQM project on Pharmaceutical Crime and specifically its study on health damage caused by illicit medicines.

Provided a successful outcome of the validation project, the new analytical tool can become an important contribution to the combat against substandard and falsified medicines. The starting point in failing clinical experience with medicines, rather than their failure in meeting chemical analytical requirements, is unique and may contribute to an estimate of the harm caused by SSFFCs.

Objective 4 (work package 9 – 13)

Methods to complement spontaneous reporting

Collection of spontaneous individual case safety reports (ICSRs) from healthcare professionals and, later, marketing authorization holders and the general public, has been the backbone of pharmacovigilance since the 1960s. The system has proven to be the most sensitive systematic approach for identification of new and particularly rare medicine-related problems in society. Systems for spontaneous reporting cannot answer some of the critical questions however e.g. about adverse reaction frequencies, groups at particular risk or safety in pregnancy. Additional methods have to be put in place to remedy the gaps in safety monitoring left by spontaneous reporting systems.

Public Health Programmes (PHP), e.g. those against malaria, HIV/AIDS and tuberculosis are established to effectively treat serious public health challenges through intensive use of medicines, and many other interventions. Spontaneous reporting does not meet the demand for safety follow-up of treatment in PHP because of reporting rates being invariably low and the necessary incidence rates not being generated.

Monitoring Medicines engaged the experts of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) to discuss the methodological approaches that would best complement spontaneous reporting and that would be feasible to introduce in LMIC and particularly in PHP. The discussions of the Committee resulted in Cohort Event Monitoring and Targeted Spontaneous Reporting being identified as methods filling the gaps and being suited for implementation in LMIC and for PHP. The deliberations of the Committee were reflected in the WHO Pharmaceuticals Newsletter 2010, No 4, p. 17 www.who.int/medicines/publications/newsletter/2010news_4.pdf

A scientific article, describing the three methods recommended by WHO for use in Public Health Programmes was later published in a peer-reviewed journal. It was written in collaboration with the WHO HIV/AIDS and tuberculosis programmes:
Pal S., Duncombe C., Falzon D., Olsson S. WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems. Drug Safety 2013; 36:75 – 81

A pharmacovigilance handbook for TB programmes

With the assistance of one of the experts of ACSoMP and the WHO anti-tuberculosis programme Monitoring Medicines developed ‘A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis’. The handbook describes in considerable detail how to implement the three preferred monitoring methods, spontaneous reporting, Targeted Spontaneous Reporting and Cohort Event Monitoring. The handbook was distributed widely to TB Programme managers in countries and national pharmacovigilance centres in the WHO Programme for International Drug Monitoring. The handbook can be downloaded from the web sites of WHO and UMC www.who.int/medicines/publications/pharmacovigilance_tb/en/. It has also been on display at many international conferences focusing on TB or pharmacovigilance e.g. as a poster at the Annual Congress of the European Respiratory Society in Vienna, September 2012.

The handbook for pharmacovigilance in anti-TB programmes was developed at a particularly suitable time. Because of the spread of multi drug-resistant tuberculosis in many countries several new but potentially toxic medicines have been introduced. Patients will be exposed to complex combinations of second-line medicines, increasing the burden of adverse drug reactions. Targeted Spontaneous Reporting is a suitable method to follow-up the safety of such experimental treatment in limited patient cohorts.

For the first time in forty years a newly developed medicine for treatment of TB was recently licensed for marketing. The medicine, bedaquiline, was licensed provided the safety of patients exposed is carefully monitored. The WHO TB programme and donors are seriously considering initiating Cohort Event Monitoring programmes of bedaquiline to establish its safety profile under normal conditions within a relatively short period of time. Additional substances under development for TB-treatment are close to being licensed. Their safety in clinical practice will need to be studied as well. Pharmacovigilance will feature in the revised WHO International Standards for TB care and the post-2015 TB strategy.

Teaching countries to use the recommended methods

Monitoring Medicines organized three training courses, in Mombasa, Kenya(2) and Kiev, Ukraine, to make pharmacovigilance centres and PHP engaged in field testing of the two methods, TSR and CEM that have been recommended by WHO to complement normal spontaneous reporting. For the training in Mombasa national pharmacovigilance and HIV/AIDS programmes were invited from Botswana, Uganda and Zimbabwe to learn about the TSR method. National pharmacovigilance and malaria programmes from Burkina Faso, Ethiopia and Kenya learned about implementation of CEM. For the Kiev training national pharmacovigilance and HIV/AIDS programmes from Belarus, Moldova and Ukraine were invited to study the CEM methodology.

After the training the representatives of pharmacovigilance and PHP in all countries were given a period of approximately three months to put together an action plan for implementation of the method on which they had been trained. Criteria for their assessment were provided. Through a process of external expert review the two best proposals from the Mombasa course (1 TSR + 1 CEM) and the best proposal from the Kiev course were selected for funding of a pilot study. The project proposal on TSR from Uganda was selected for implementation as were the CEM proposals from Kenya and Belarus. Belarus wrote a public description of its project which was published on the web site of WHO Regional Office for Europe. www.euro.who.int/en/where-we-work/member-states/belarus/news/news/2013/01/monitoring-the-safety-of-antiretroviral-medicines-in-belarus

A consistent feed-back received from all countries after the training and the joint work on project plans was that the exercise had contributed to much greater understanding between the pharmacovigilance and PHP programmes. For the countries selected for funding of their pilot projects that wider understanding of the issues of pharmacovigilance in PHP spread to the implementation sites and had a lasting effect.

The Targeted Spontaneous Reporting method was picked up by the WHO HIV/AIDS programme and suggested for implementation in Côte d’Ivoire, Kenya, Laos and Vietnam. These projects are funded by a grant from the Bill and Melinda Gates Foundation, also expressing support for the particular suitability of TSR in many PHPs.

On-site support to pilot projects

Experts teams from WHO and UMC visited the implementation sites for TSR in Uganda and CEM in Kenya and Belarus. The site visits gave some further attention and prominence to the pharmacovigilance projects locally and gave the team members opportunities to interact directly with clinicians and to learn about implementation challenges. Team members could respond to questions on methodological and data management issues. They were also given opportunities to meet high representatives of Ministries of Health and could explain to them the merits of the supported surveillance methods and the benefits of collaboration between pharmacovigilance and public health programmes.

The team visiting Belarus could initiate a discussion about the interest to extend the present CEM pilot programme on anti-retroviral medicines to a cohort of patient also suffering from tuberculosis. A great interest to be involved in such a project was demonstrated both by clinicians at the implementation sites and the pharmacovigilance centre professionals. An extension of the CEM programme along the lines discussed at the site visit is currently being discussed with the WHO TB programme.

Results from of the implementation of the pilot

Interim results from Belarus, Kenya and Uganda, responsible for the pilot implementation of Cohort Event Monitoring and Targeted Spontaneous Reporting respectively, indicate that the methods are considered appropriate for their intended purpose and feasible for roll-out in the settings.

The positive experience of CEM for HIV/AIDS in Belarus is prompting the WHO TB programme to support an extension of the programme to monitor also patients on treatment for multi-resistant tuberculosis and for the introduction of new drug therapies for TB. Pharmacovigilance programme officers from Belarus are being engaged in relevant training initiatives. This is an example of methodological progress in patient safety leading the way for the introduction of new treatment options for particularly vulnerable patients.

The implementation of CEM in Kenya has demonstrated a keen interest from the malaria programme to be involved in safety follow-up of patients and drop-out rates proved to be very low in the pilot.

With the pilot implementation of CEM in Belarus and Kenya the Monitoring Medicines project has built competence and capacity for active surveillance of newly introduced medicines to complement spontaneous reporting. A feasible model for the introduction of such methods in countries has been demonstrated. Activities are already on the way to apply what has been learned in new settings and beyond the pilot countries. Ukraine, one of the countries included in the CEM training, has also reported much improved performance of their HIV/AIDS programme in the safety monitoring of drug treatment.

The introduction of TSR in Uganda has injected vitality into the collaboration between the national programmes for pharmacovigilance and HIV/AIDS and clinicians responsible for care of HIV patients have responded by increasing their reporting of suspected adverse reactions exponentially. Results have been generated to inform programme managers of the benefit/harm situation with the newly introduced tenofovir-based treatment and they are now recommending an expansion of the TSR initiative to other areas of Uganda.

A data management tool to support Cohort Event Monitoring

When WHO first suggested CEM to be pilot tested in Africa by Tanzania and Nigeria, UMC developed a web-based data management tool, CemFlow, to record patient, exposure and event information. Because of inadequate access to internet in many African countries, particularly broad-band internet, CemFlow was largely inaccessible or time consuming and frustrating to use. Monitoring Medicines commissioned the IT-development unit of UMC to upgrade CemFlow allowing data input also in off-line mode. In its new version CemFlow was well accepted by its users. Currently the tool has been used to support CEM programmes in Nigeria, Tanzania, Ghana, Zimbabwe, Kenya and Belarus. Negotiations for an extension of its use to a malaria programme in Vietnam are ongoing.

Establishing a HIV pharmacovigilance database

Damage to the immune system from HIV can result in the development of opportunistic infections (OIs), infections common to HIV/AIDS that occur when the body's immune system is weakened. Symptoms vary and may include such different signs as cold sores and extreme weight loss. Many HIV-positive people are also infected with other diseases called co-infections. Patients who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission: percutaneous exposure to blood, sexual intercourse, and from a mother to her infant. Infection with HCV can be asymptomatic, self-limiting, or progress to cirrhosis or cancer.

Side effects of ART may occur after the first dose, while other side effects may not show up until one has been on the medicine for a long time. How are side effects reported? When drugs are first studied, every side effect is recorded, even if it cannot be directly linked to the drug being studied. If side effects only become apparent after the drug has been approved, as with lipo-dystrophy, the drug leaflet may not have this latest information

The project lead by Copenhagen HIV Programme to create a pharmacovigilance database, using HIV ADR data, by merging HIV ADR from several sources into a common database storage of information of ADRs to ARVs (preferred terms, requiring medical education will be used). To develop information technology tools to easily search, retrieve and evaluate information from this database via a publicly available website and develop modules on website to test knowledge about such reactions.

The project has now developed an online resource for health care professionals in the field of HIV, providing access to: the latest information on ARV side effects and toxicity, Easy-to-understand review articles, published research papers and guidance documents on issues of ARV toxicity, risk evaluation tools. The tools and website we developed are referenced in the EACS European AIDS Clinical Society (http://eacsociety.org/Guidelines.aspx) new version to be released in October this year.

Reference: http://www.hivpv.org/

The website has received a new and better design.

List of Websites:
Website: www.monitoringmedicines.org

Partners web address

MPA: http://www.lakemedelsverket.se/
WHO: http://www.who.int/en/
NPSA: http://www.npsa.nhs.uk/
Elliot Brown: http://www.ebconsulting.co.uk/
University of Ghana: http://www.ug.edu.gh/
Lareb: http://www.lareb.nl/
UCPH: http://www.ku.dk/
CAPM: http://www.capm.ma/
PPB: http://www.pharmacyboardkenya.org/
Zuellig: http://zuelligfoundation.org/
UMC: http://www.who-umc.org/

Contacts

Project Coordinator: Sten Olsson (UMC) [e-mail]
Project Manager Ennita Nilsson (UMC) [e-mail]
Project lead Partner Shanthi Pal (WHO) [e-mail]
Coordinator organization name:
Stiftelsen WHO Collaborating Centre for International Drug Monitoring
Box 1051, SE-751 40 Uppsala, Sweden
Visiting address: Bredgränd 7, Uppsala
Tel [phone] (direct)
Fax [phone]

final1-publishable-summary-report-monitoring-medicines.pdf

Documents connexes

• final1-publishable-summary-report-monitoring-medicines.pdf