Drug Safety

, Volume 37, Issue 10, pp 743–759

Teaching Pharmacovigilance: the WHO-ISoP Core Elements of a Comprehensive Modular Curriculum

  • Jürgen Beckmann
  • Ulrich Hagemann
  • Priya Bahri
  • Andrew Bate
  • Ian W. Boyd
  • Gerald J. Dal Pan
  • Brian D. Edwards
  • I. Ralph Edwards
  • Kenneth Hartigan-Go
  • Marie Lindquist
  • John McEwen
  • Yola Moride
  • Sten Olsson
  • Shanthi N. Pal
  • Rachida Soulaymani-Bencheikh
  • Marco Tuccori
  • Claudia P. Vaca
  • Ian C. K. Wong
Special Article

DOI: 10.1007/s40264-014-0216-1

Cite this article as:
Beckmann, J., Hagemann, U., Bahri, P. et al. Drug Saf (2014) 37: 743. doi:10.1007/s40264-014-0216-1

1 Introduction

The importance of pharmacovigilance (PV) for safe medicines and their safe use has increasingly been recognised during the last few years [1]. PV has been subject of intense research and regulation. In particular, it has earned more and more importance and attention in low-resource countries. This is largely due to the globalisation of trade and the availability of new, highly effective but potentially harmful chemical medicinal products in those parts of the world where traditional treatments, in particular herbal or other complementary remedies, used to prevail. A plethora of publications, guidelines and information about newly observed or further investigated adverse drug reactions (ADRs) from all over the world creates a growing burden for people working with medicines or patients to keep abreast of this development. Largely due to the global availability of information through the Internet, patients are nowadays more and more critical and often concerned about, or even frightened of, potential ADRs of their medicines. This poses an additional demand on the up-to-date capacities of their doctors and other healthcare professionals (HCPs). A particular challenge is the multidisciplinary character of PV which requires know-how in topics as different as molecular mechanisms of ADRs, clinical medicine, pharmacoepidemiology, information technology, pharmaceutical manufacturing, legal aspects, public health situations on various levels, and traditions in different regions of the world. Also, theoretical knowledge needs supplementing with experience and practical skills.

There are various stakeholders with specific and different interests requiring PV training, particularly industry, HCPs and their organisations, local health workers, regulators, policy makers, healthcare-related non-governmental organisations (NGOs), researchers in pharmacology or other healthcare disciplines, and teachers at universities and hospitals, both in industrialised and in developing countries. In this complex situation there is a growing need for PV capacity building, particularly by professional training through a broad range of high-quality PV courses with different focuses and different levels of detailing.

Several PV seminars and educational programmes have already been offered for many years by a range of institutions, societies and commercial entrepreneurs. Information about such courses can be readily obtained via the advertising flyers or the Internet. Such material typically outlines about 10–15 main topics and provides a few paragraphs addressing hands-on exercises, if any, together with information about the lecturers and their qualification, the duration of the course, logistic and financial aspects and the issue of homework, exams and certificates. Although there is a substantial overlap in the main topics covered by those PV courses, there are also significant differences between them. Furthermore, the descriptions of the topics, e.g. ‘signal detection’, are very broad. They have to be filled with detailed substance by the lecturers, reflecting their opinion of what is important, but also according to their individual expertise, preference or even personal purposes. Consequently, courses not only about PV as a whole but also about specific topics can be designed extremely differently.

For this reason, people working in public health or other fields related to drug safety, and who are responsible for teaching and who feel a need for widespread and in-depth education in this area, will often be unsure about the topics that should most importantly be covered by a course. Also, they may appreciate advice on how much time, which educational material and what kind of specific expertise of the trainers are needed so that the participants can achieve relevant knowledge and skills on defined levels. Even trainers with indisputable competence in specific areas of PV may not always present their topic within the wider context of PV, i.e. with explanation how other areas adjoin their field and how the topics relate to each other.

It is with this background that experts working in various fields of medicine safety around the world took the initiative and have co-operated to create a comprehensive, detailed and balanced curriculum of PV. Some are appointed members in PV committees associated with the World Health Organization (WHO) or work at its collaborating centres. Others are members of the Executive Committee of the International Society of Pharmacovigilance (ISoP) or its Education and Training Project (ETP) group, or work in institutions dedicated to PV. Our purpose was to provide an inventory and overview of the scope of PV, including relatively new topics such as pharmacogenomics, consumer reporting of ADRs, risk management and WHO-led international projects at several levels of specificity. It was also intended to propose a range of tasks for practical training to reinforce theoretical knowledge acquired. This paper presents the result of this work.

2 Development of the Curriculum

The curriculum makes use of several relevant, already existing packages of topics and concepts of PV teaching. There are already well-established courses, such as those organised by the WHO collaborating centres in Uppsala [2], Rabat and Accra, the University of Hertfordshire [3], the Drug Safety Research Unit (DSRU) [4] or the London School of Hygiene and Tropical Medicine (LSHTM) [5]. Also, a teaching programme ‘EU2P’ is now available in the EU [6]. Furthermore, courses of general interest or with a focus on specific methods, have been offered by ISoP and the International Society of Pharmacoepidemiology (ISPE) during their annual or mid-year meetings. WHO, often in collaboration with the Uppsala Monitoring Centre (UMC) or other collaborating centres, have conducted several training courses in low- and middle-income countries in Africa, Asia and Latin America where the focus was on safety of medicines used for the treatment of important infectious diseases or on setting up new PV centres. Topics of specific relevance for industry and regulators in industrialised countries have usually been covered by the Drug Information Association (DIA) [7] and other commercial conference organisers.

The development of a core curriculum was also inspired by comprehensive overviews and textbooks, which provided ideas and information material about the broad scope of PV. For specific themes and sections, many suggestions have been retrieved from textbooks with specific focuses. Standard sources of information about specific drug-related risks include various reference books. For practical issues concerning PV within the pharmaceutical industry and their relation to drug regulatory authorities, a couple of guidelines were used as reference sources. Also, sets of specific guidance documents were consulted. Single review articles with a wide scope which seemed useful for didactical purposes, were mainly identified in the journals Drug Safety and Pharmacoepidemiology and Drug Safety. An overview of these primarily-used literature sources is given in Table 1.
Table 1

Tabulated overview of primarily-used literature sources

Literature category

Author(s), editor(s)

Title

References

Textbooks on the broad field of pharmacovigilance

Talbot J, Aronson JK (eds.)

Stephens’ detection and evaluation of adverse drug reactions

[8]

Andrews E, Moore N (eds.)

Mann’s pharmacovigilance

[9]

Textbooks on specific aspects of pharmacovigilance

Strom BL, Kimmel SE, Hennessy S (eds.)

Pharmacoepidemiology

[10]

Van Boxtel CJ, Santoso B, Edwards IR (eds.)

Drug benefits and risks

[11]

Rawlins MD

Therapeutics, evidence and decision-making

[12]

Reference books

Aronson JK (ed.)

Meyler’s side effects of drugs

[13]

Sweetman SC (ed.)

Martindale - the complete drug reference

[14]

World Health Organization

WHO model formulary

[15]

Compilations of guidances

CIOMS - Council for International Organizations of Medical Sciences

Publications on drug development and use

[16]

ICH - International Conference on Harmonisation

Guideline index batch E

[17]

ENCePP - European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

ENCePP guide on methodological standards in pharmacoepidemiology

[18]

EMA - European Medicines Agency

Good pharmacovigilance practices

[19]

MHRA - UK Medicines and Healthcare products Regulatory Agency

Good pharmacovigilance practice guide

[20]

US FDA - Food and Drug Administration

Guidance, compliance and regulatory information: drug safety

[21]

Cobert B

Cobert’s manual of drug safety and pharmacovigilance

[22]

University of Ghana Medical School

WHO’s PV Toolkit

[23]

WHO Department of Essential Medicines and Healthcare Products

Publications on pharmacovigilance

[24]

ISPE - International Society of Pharmacoepidemiology

Guidelines for good pharmacoepidemiology practices

[25]

Review articles in journals

 

Drug Safety - official journal of the International Society of Pharmacovigilance

[26]

 

Pharmacoepidemiology and Drug Safety - official journal of the International Society of Pharmacoepidemiology

[27]

For the purpose of supporting trainers and participants, a more extensive list of references has also been compiled. Many of these references are chapters of comprehensive books [8, 9], and provide overviews of the respective topic. Among journal articles, emphasis is put on systematic reviews. Guidelines and recommendations are preferably cited if they were developed by worldwide acting organisations, such as the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference on Harmonisation (ICH). Considering public health issues relevant to low- and middle-income countries, several guidelines and recommendations are also drawn from printed material issued by the WHO and related organisations. Another selection criterion was freely available information from the Internet, particularly guidelines that are updated from time to time.

The development of the PV curriculum has been a continued effort, started by a few of us some years ago, with several additional experts subsequently contributing to the project. There was no formal procedure for reaching a consensus, such as the Delphi method; however, as many proposals as possible were taken into account.

3 Results

The curriculum presented here includes a main component consisting of modules for theoretical lecture-based training and a minor component with suggestions for hands-on exercises. The theoretical component has a hierarchical and modular structure with evenly divided tiers, and outlined in Table 2. There are 15 chapters of about equal length (hierarchy level I) with four sections each of about equal length again, making a total of 60 sections (hierarchy level II). All sections are composed of four to six subsections, i.e. approximately 300 subsections altogether (hierarchy level III).
Table 2

Core elements of the modular pharmacovigilance curriculum for lecture-based teaching

1

What is and Why do we Need Pharmacovigilance (PV)?

1.1

Subject and scope of PV

1.1.1

Context, definition and purpose of PV

1.1.2

The adverse event (AE) and adverse drug reaction (ADR) at the centre of PV

1.1.3

The wide scope of PV

1.1.4

Persons and parties involved in PV–their concerns, competences and interactions

1.1.5

The increasing complexity and challenges of PV

1.2

History of PV: important ADRs and methodological and organisational developments

1.2.1

The origin of modern PV: thalidomide and the emergence of ADR reporting and drug legislation

1.2.2

Major disasters and their impact on PV: OCs–VTE, HRT–breast cancer, cerivastatin–rhabdomyolysis, coxibs–cardiovascular death, etc

1.2.3

The shaping of institutions, international cooperation and information exchange

1.2.4

Focus on methods: spontaneous reporting, pharmacoepidemiology, data bases and linkage, data mining, genetic testing

1.2.5

Focus on medication errors, counterfeiting and patient safety

1.2.6

Focus on proactive risk management and legislation

1.3

ADRs and public health

1.3.1

Effects of ADRs in general for patients’ health and treatment and for drug development and acceptance

1.3.2

High risk patient groups, drug groups and settings

1.3.3

Statistics of drug-related harm to patients’ treatment, health and life

1.3.4

Statistics of financial and other resources needed due to drug-related harm

1.3.5

Statistics of wrong medication leading to drug-related harm

1.3.6

Ecological consequences of drug disposal

1.4

Limited risk prediction from molecular analogy, pre-clinical studies and pre-marketing clinical trials

1.4.1

Risk prediction by drug class analogy

1.4.2

Pre-clinical in vitro tests

1.4.3

Animal toxicology, concept and options

1.4.4

Animal toxicology, limitations

1.4.5

Pre-marketing clinical trials, concept, options, limitations

2

Fundamental Clinical Aspects of ADRs

2.1

Types and mechanisms of ADRs

2.1.1

‘Type A’ (pharmacological): exaggeration of desired effect or effect at different site or of different type

2.1.2

‘Type B’ (hypersusceptibility/idiosyncratic)

2.1.3

Other types of ADRs: poisoning, drug resistance or dependence, carcinogenic or teratogenic effect, infection

2.1.4

Other ADR classifications: according to time course, dosage, patient susceptibility, mechanism, expectedness

2.1.5

Seriousness and severity of ADRs

2.1.6

Surrogate markers as diagnostic indicators, non-serious ADRs or precursors of serious ADRs

2.2

Pharmacogenetic causes of inter-individual variability in the susceptibility to ADRs

2.2.1

Definition, biochemical basis, scope and challenges of pharmacogenetics

2.2.2

Genetic polymorphism of enzymes involved in phase I drug metabolism: CYP 1, 2 and 3 oxygenases

2.2.3

Genetic polymorphism of enzymes involved in phase II drug metabolism and in drug transport

2.2.4

Genetic polymorphism of ion channels, receptors and enzymes involved in pharmacodynamics

2.2.5

Genetic polymorphism of genes responsible for immunological and other idiosyncratic Type B ADRs

2.2.6

Drug development and genetically individualised treatment: tailored indications, tests, safeguards

2.3

Non-genetic risk factors for ADRs and complex interactions

2.3.1

Young and old age, gender, social factors

2.3.2

Target- and concomitant diseases including virus infection, history of drug intolerance, temporary situations

2.3.3

Pregnancy and teratogenic effects

2.3.4

Drug–drug interactions at same molecule/site–pharmacokinetic or pharmacodynamic, synergistic or antagonistic

2.3.5

Complex interactions between drugs affecting different molecular sites or organs and other risk factors, e.g. renal or hepatic impairment

2.3.6

Drug interactions with food, alcohol, grapefruit, vitamins as food additives, smoking, sun exposure

2.4

Clinical management of ADRs

2.4.1

Avoiding ADRs of individual patients à priori: personal risk assessment and precautionary measures

2.4.2

Treating symptoms and assessing and eliminating possible causes in case of ADR suspicion

2.4.3

Identifying the ‘culprit’ in case of ADR suspicion

2.4.4

Continuing treatment after an ADR was considered likely

3

Important ADRs and ‘Risk Driving’ ADRs of Important Medicines

3.1

Serious ADRs at organ classes where ‘Type B’ reactions are important. Most involved drugs

3.1.1

ADRs affecting the skin

3.1.2

ADRs affecting haematopoiesis, blood cells and haemostasis

3.1.3

ADRs affecting the liver and the biliary system

3.1.4

ADRs affecting the kidney and urinary tract

3.1.5

ADRs affecting the respiratory tract

3.2

Important ADRs at organ classes where ‘Type A’ reactions are most important, and the mostly involved drugs

3.2.1

ADRs affecting the gastrointestinal tract

3.2.2

ADRs affecting the endocrine system and metabolism

3.2.3

ADRs affecting the cardiac and the vascular system

3.2.4

ADRs affecting the nervous system

3.2.5

ADRs affecting vision, hearing and taste

3.2.6

Tumorigenic and teratogenic effects

3.3

Focus on ADRs of anti-infectives particularly important in limited resource settings and of vaccines

3.3.1

ADRs of anti-HIV medicines

3.3.2

ADRs of anti-tuberculosis medicines

3.3.3

ADRs of anti-malaria medicines

3.3.4

ADRs of medicines used in neglected tropical diseases

3.3.5

Vaccines: peculiarities of their ADRs in general, lack of effectiveness, injection site reactions

3.3.6

Vaccines: generalised ADRs due to immunological reactions, toxicity or replication of infective agents

3.4

‘Risk drivers’ of important drugs for common illness and chronic diseases, biologicals, herbals

3.4.1

ADRs of medicines used in common cold (fever, headache, pain, cough)

3.4.2

ADRs of medicines used in respiratory disorders (asthma, COPD)

3.4.3

ADRs of medicines used in rheumatic disorders (back pain, osteoarthritis)

3.4.4

ADRs of medicines used to treat anxiety, depression and mental discomfort

3.4.5

ADRs of medicines used in metabolic syndrome (hypertension, dyslipidaemia, obesity, diabetes)

3.4.6

ADRs of widely used herbals

4

‘Individual Case Safety Reports’ (‘ICSRs’)

4.1

Concerns about ADRs: medical, psychological and regulatory background and reasons for reporting

4.1.1

Definition of ICSRs and their ‘typology’ with respect of provenance and subject matter

4.1.2

Place value of ICSRs in PV: insights they can and cannot provide and their impact on drug regulation

4.1.3

Healthcare professionals as reporters: their knowledge, diagnostic means, motivations and fears

4.1.4

Patients as reporters: their concerns, expectations, specific knowledge and observations

4.1.5

MAHs as reporters: their information background, sources and obligations

4.1.6

‘Culture’, stimulation and organisation of spontaneous ADR detection and reporting

4.2

Contents, structure and validity of reports and reporting procedures

4.2.1

Minimum necessary information, structured fields on one-page reporting forms, overview of ICH E2B

4.2.2

Case narratives

4.2.3

Case follow-up and validation

4.2.4

Literature reports

4.2.5

Use of AE/ADR terminologies and definitions and drug dictionaries by primary reporters

4.2.6

Use of technical means for reporting

4.3

Case assessment

4.3.1

Completeness, accuracy and precision of the report

4.3.2

Certainty of the diagnosis

4.3.3

Seriousness and severity of the AE/ADR

4.3.4

Causality of the AE: purpose, criteria and problems of the assessment

4.3.5

Causality of the AE: common general and specific assessment methods, outcome ratings, shortcomings

4.3.6

Expectedness of the AE/ADR

4.4

Reports related to vaccines, herbals and specific situations

4.4.1

Reports about adverse events following immunisation (AEFI): specific features

4.4.2

Causality assessment with AEFI

4.4.3

Reports about AEs/ADRs with herbal medicines

4.4.4

Reports about AEs/ADRs related to pregnancy and lactation

4.4.5

Reports about drug-drug interactions, drug abuse and poisoning

5

Pharmacovigilance in Clinical Trials

5.1

Characteristics of pharmacovigilance in clinical trials

5.1.1

Types, objectives and limitations of pre-authorisation studies

5.1.2

Categories of primary hazard data

5.1.3

Safety in focus of early drug development, in particular first-into-man studies

5.1.4

Prevailing patient groups and medicines according to current public health needs

5.1.5

Persons and bodies involved, responsibilities, co-operation

5.2

Collection of hazard data: planning and practical realisation

5.2.1

Study protocol, investigator brochure, informed consent form

5.2.2

Specific vulnerable (sub-) populations

5.2.3

Treatment-related risks

5.2.4

Test parameters

5.2.5

Strategies of data collection

5.2.6

Data presentation

5.3

Risk assessment

5.3.1

Assessment of individual AE observations

5.3.2

Detection of specific ADRs as harmful properties of IMPs and non-IMPs

5.3.3

Statistical quantification of safety data from individual studies

5.3.4

Data pooling and ADR frequency estimation

5.3.5

Development of labelling

5.4

Guidance and regulatory framework

5.4.1

Guidelines and directives

5.4.2

Key documents at the start and during a study

5.4.3

Key documents at and after the end of a study

5.4.4

Reporting obligations

5.4.5

Other communication activities

6

Counterfeiting, Quality Defects and Medication Errors

6.1

Counterfeiting, demarcation against manufacturing-related quality defects

6.1.1

Definition of substandard/spurious/falsely labelled/falsified/counterfeit (SSFFC) medicines and respects of counterfeiting

6.1.2

Pattern and scale of counterfeiting; consequences, in particular antimicrobial resistance

6.1.3

Methods used by counterfeiters

6.1.4

Technical, organisational and political anti-counterfeit measures

6.1.5

How the legitimate MAH can and should help

6.1.6

How to manage unintentional quality defect problems

6.2

Medication error (ME): definition, impact, detection

6.2.1

Definition and typology of MEs, demarcation from off-label use

6.2.2

ME statistics and impact on public health

6.2.3

Victims, medical situations and medications typical for MEs

6.2.4

Detection of MEs: national spontaneous reporting schemes for professionals

6.2.5

Detection of MEs: methods in specific healthcare settings for professionals

6.2.6

Detection of MEs: patient reporting

6.3

ME reports: description and assessment

6.3.1

Description of clinical patient aspects

6.3.2

Description of procedural and patient adherence aspects

6.3.3

Assessment of the proximal/immediate cause

6.3.4

Contributing system factors

6.3.5

Root cause analysis (RCA)

6.3.6

Assessment of avoidability/preventability

6.4

Preventive measures

6.4.1

Education and information material

6.4.2

Culture of the handling of ME incidences and learning from them

6.4.3

Global political and regulatory activities

6.4.4

Local and technical organisational measures

6.4.5

Specific aspect: conflict, synergy and harmonisation with classical PV (challenges)

6.4.6

Legal, ethical and confidentiality aspects

7

Spontaneous ICSR Reporting Systems (SRS)

7.1

Definition, settings, potential and limitations of SRS

7.1.1

Definition, potential and achievements of SRs

7.1.2

SRS settings and resources; sources of spontaneous reports (SRs)–healthcare professionals (HCPs), patients, companies, media

7.1.3

Detecting, documenting and reporting of AEs/ADRs: methods, forms, routes, software

7.1.4

Places and institutions collecting spontaneous reports

7.1.5

Informational limitations of SRs: incomplete, no denominator, biases; proposed caveats

7.1.6

Stimulated, mandatory, solicited and targeted reporting

7.2

Computerised ICSR databases: requirements and structure, administration

7.2.1

Typical ICSR databases: relational model, SQL language

7.2.2

Structure (e.g. separate patient, literature, study reports), scalability, performance

7.2.3

Stability, resilience, security, storage, maintenance

7.2.4

Database management systems: requirements, available report management software

7.2.5

Quality assurance: duplicate-, syntax-, coherence-check, tracking facilitation and follow-up

7.2.6

Specific requirements of pharmaceutical company databases, e.g. reporting functions

7.3

Data transmission and entry

7.3.1

Forms and formats of ICSR transmission: one-page forms, email, phone, ICH E2B, ICH M2

7.3.2

Coding of diseases and ADRs using terminologies WHO-ART, ICD, MedDRA

7.3.3

Coding of drugs using classifications and dictionaries: ATC, WHO-DD (enhanced), EVMPD

7.3.4

Special issues: quality check, anonymisation, case IDs, lab data tables, narratives, language

7.3.5

Correspondence with reporters: confirmation of receipt, requests for additional data

7.4

Data retrieval, descriptive statistics, access and confidentiality

7.4.1

Electronic techniques of data retrieval: formats, networks, browsers and other tools, SGML language

7.4.2

Serving the searcher: standardised entry screens, search support, stratification of data

7.4.3

Descriptive statistics (presenting numbers; not analysing and testing)

7.4.4

Format of retrieval results: line listings, summary tabulations, profiles, sometimes ICSRs

7.4.5

Graded access according to data and interested parties, proactive publications; confidentiality

7.4.6

Important accessible databases, terms of access: WHO/UMC, others

8

Signal Detection and Management

8.1

Definition of a signal; sources, potentials, detection by non-statistical medical means

8.1.1

What is a ‘signal’?–definitions by WHO, CIOMS, others

8.1.2

What a signal may indicate: new ADR, higher severity or frequency, risk factors, wrong medication, product faults

8.1.3

Sources of information which may constitute a signal: ADR databases, case-control surveillance, other sources

8.1.4

Basic requirements for signal detection and management

8.1.5

Stakeholders in the signal detection and management process

8.1.6

Detection of signals for new ADRs from ADR case-series by non-statistical medical means

8.2

Disproportionality statistics for signal detection in spontaneous ISCR databases

8.2.1

Principles of statistical data mining in ICSR databases

8.2.2

Calculating proportional reporting ratios (PRRs) and reporting odds ratios (RORs)

8.2.3

Bayesian methods: information component (IC) and gamma poisson shrinker calculating EBGM

8.2.4

Calculating statistical significance of disproportionate reporting and confidence intervals

8.2.5

Determining sensitivity and specificity of signal detection by defining minimum number of reports, extent of disproportionality and statistical significance

8.2.6

Strengths and weaknesses of different data mining methods, e.g. vulnerability to low and high numbers

8.3

Special issues in disproportionality approaches

8.3.1

Applying disproportionality statistics to ICSRs selected by quality, ADR (group), drug (class), indication, age. Excluding known ADRs

8.3.2

Detecting complex associations: drug-drug interactions, other risk factors, syndromes

8.3.3

Combining ICSR and drug utilisation data (e.g. from IMS) as denominator

8.3.4

Applying disproportionality statistics to longitudinal patient record and exposure data

8.3.5

Sequential probability ratio tests (SPRTs); tree-based scan statistic (ScanTree)

8.3.6

Available software for data mining

8.4

Prioritisation, validation, assessment, risk confirmation or refusal, communication, further action

8.4.1

Prioritisation according to evidence and potential public health impact (seriousness, drug utilisation)

8.4.2

Validation by checking report quality, duplicates, plausibility, consistency, other information, biases

8.4.3

Assessment, absolute: clinically plausible causality, meaning, impact, preventability

8.4.4

Assessment, relative: relating number of reports to utilisation, comparing with other drugs

8.4.5

Consequences of confirmed signals: communication, further investigation, options of action

9

Post-Authorisation Observational Studies and Clinical Trials in PV

9.1

Definition and objectives of post-authorisation studies, general requirements, specific studies

9.1.1

Definition of post-authorisation studies, non-interventional studies, pharmacoepidemiology

9.1.2

Post-authorisation studies for confirmation of signals and providing data on ADR frequency and causality

9.1.3

Observational studies: general formal and scientific requirements, opportunities, limitations

9.1.4

Population-oriented post-authorisation studies: disease studies, drug utilisation studies

9.1.5

Post-authorisation randomised clinical trials, in particular ‘large simple trials’ (LSTs)

9.2

Important observational studies and their strengths and weaknesses

9.2.1

Cohort studies in general: design, conduct, statistical analysis and presentation of results

9.2.2

Cohort-event monitoring (CEM), including PEM as specific applications

9.2.3

Dealing with different hazard functions and different exposure times (person years)

9.2.4

Case-control studies: design (including nested in cohorts), conduct, statistical analysis and presentation of results

9.2.5

Rationale and approaches for within-patient study designs, e.g. case-crossover studies

9.3

Bias, confounding and effect modification in observational studies

9.3.1

Definition of bias and confounding and principles of dealing with them

9.3.2

Important biases: selection (e.g. referral) bias, information (e.g. recall) bias, detection bias; how to deal with these biases

9.3.3

Important confounders, in particular confounding by indication

9.3.4

How to deal with these confounders (e.g. matching, propensity scoring, sensitivity analysis)

9.3.5

Effect modification: principles of measurement and presentation in a study report

9.3.6

Novel designs avoiding with these problems: within-subject or case-crossover designs

9.4

Sources of study subjects and data

9.4.1

De novo data collection (interviews, patient charts), spontaneous reports, surveys, CEM

9.4.2

Large automated health databases (LADs) or electronic medical records: typical structure

9.4.3

Important accessible LADs in North America, Europe and Asia

9.4.4

Registers of diseases, specific ADRs or exposure; pregnancy registers

9.4.5

Record linkage: options and problems (e.g. compatibility, confidentiality)

9.4.6

Choosing data and methods for the estimation of ADR frequencies

10

Benefit-Risk Assessment

10.1

‘Benefit-risk’: definitions, methodological approaches; disease as criterion of benefit

10.1.1

Definition of benefit, harm, chance, risk and their components magnitude, duration, likelihood

10.1.2

Initiatives to develop methods for benefit-risk assessment: PROTECT, BRAT

10.1.3

Frameworks for benefit-risk analysis: Ashby-Smith Bayesian approach, MCDA, SMAA

10.1.4

Complexity of disease-related risks: multiplicity, time dependence, likelihood, subjectivity

10.1.5

Disease-related harm and risk as targets of drug treatment and criteria of benefit and chance

10.2

Drug-related risks (ADRs): analysing, weighting and combining their components

10.2.1

Complexity of ADR-related risks: multiplicity, time dependence, likelihood, subjectivity

10.2.2

Measuring and weighting disease- and drug-related objective and subjective ‘instantaneous harm’

10.2.3

Considering aspects of time: point in time (hazard function), duration of harm

10.2.4

Combining harm and likelihood: the risk (due to drugs as well as diseases)

10.2.5

Weighting, combining, comparing risks using single metrics, or ‘currencies’, and ‘risk equivalents’

10.2.6

Typical discrete and continuous measures of harm: deaths, incidents, hospitalisations, QALYs, etc.

10.3

Balancing benefit/chance vs. harm/risk and comparing different treatment options

10.3.1

Principles of estimating benefit/chance in terms of reducing disease-related harm/risk using single metrics

10.3.2

Expressing benefit/chance and risk using indices like NNTand NNH, adjusted for utility, if applicable

10.3.3

Using the semi-quantitative Markov and Kaplan–Meier methods, including aspects of time

10.3.4

Estimating the difference between risks from untreated disease and treated disease plus ADRs; calculating the INHB

10.3.5

Comparing those differences across alternative treatment options: ‘indirect/mixed treatment comparisons’

10.3.6

Combining and balancing disease-related harm/risks and drug-related benefit/chance and ADRs on the public health level

10.4

Taking into account preferences of stakeholders, uncertainties and options for actions

10.4.1

Determining preferences vs. benefit/chance and harm/risk of different stakeholders: preference values; utility surveys

10.4.2

Non-pharmacological and indirect risks: misuse, errors, further complications

10.4.3

Options for improving the chance-risk balance and their likely impact; aspects of feasibility

10.4.4

Uncertainties in the underlying data: level of evidence, confidence intervals; applying the Probabilistic Simulation Method (PSM)

10.4.5

Analysing sensitivity: worst case–best case scenarios; considering the precautionary principle

10.4.6

Making chance-risk estimates understandable: visualisation and communication

11

Pharmacovigilance and Risk Management Systems, Risk Management Plans (RMPs), Inspections

11.1

Pharmacovigilance systems: definition, stakeholders and operation

11.1.1

Definition and elements

11.1.2

Contents of the ‘Pharmacovigilance System’ document, masterfile concept

11.1.3

Pharmacovigilance systems of pharmaceutical companies, marketing authorisation holders (MAHs) and distributors

11.1.4

Pharmacovigilance systems of regulatory authorities

11.1.5

Standard operating procedures (SOPs)

11.1.6

Maintenance of the pharmacovigilance systems

11.2

Product-related risk management systems

11.2.1

Rationale for establishing risk management systems and objectives

11.2.2

Establishing a risk management system: starting point and responsibilities

11.2.3

Characterisation of the risk profile

11.2.4

Risk management during the lifecycle of a drug, planning of PV activities, updating the risk management system

11.2.5

Legal basis and guidelines, role of relevant stakeholders and partners

11.3

Specific product-related RMPs; other tools and activities

11.3.1

Scope, definitions and responsible persons and institutions to establish risk management tools: RMP, REMS, others

11.3.2

Elements of risk management tools: safety specification, pharmacovigilance plan, risk mitigation measures; SmPC and PIL

11.3.3

When to establish and update a risk management tool and pharmacovigilance plan

11.3.4

Implementation, monitoring and assessing effectiveness of risk mitigation measures

11.3.5

Communication

11.4

Pharmacovigilance inspections and audits, quality assessment

11.4.1

Purpose, frequency and actors

11.4.2

Indicators of capacity and performance of the pharmacovigilance system

11.4.3

External inspections by competent authorities

11.4.4

Internal audits in companies and regulatory authorities

11.4.5

Quality assurance and benchmarking processes

11.4.6

Legislation and guidelines

12

Industry and Regulatory Authorities, Mandatory Procedures from Legislation

12.1

Facilities at pharmaceutical companies, marketing authorisation holders, wholesalers and distributors

12.1.1

Pharmacovigilance system and SOPs, crisis management plan

12.1.2

QPPV, staff resources (scientific and administrative), financial resources, technical equipment

12.1.3

Databases (ADR reports), performance tools, statistical tools and methods for analyses

12.1.4

Product-related archives, correspondence archives, library and access to electronic literature databases

12.1.5

Communication tools, contact details, Internet access, fax, phone, video conference services

12.2

Mandatory tasks and procedures from legislation at industry

12.2.1

ADR collection and reporting to competent authorities, signal detection and management

12.2.2

Study reports, Periodic Safety Update Reports (PSURs), Periodic Benefit Risk Evaluation Reports (PBRERs)

12.2.3

Other documents: DSUR; RMP, REMS; renewal dossiers; reports on request

12.2.4

Regular benefit/chance-to-harm/risk assessment

12.2.5

Decision making, monitoring effectiveness of measures taken

12.2.6

Quality management, determination and assessment of performance indicators, training

12.3

Facilities at regulatory authorities

12.3.1

Pharmacovigilance system and SOPs, crisis management plan

12.3.2

Staff resources (scientific and administrative), technical equipment

12.3.3

Databases (ADR reports), statistical tools and methods for analyses

12.3.4

Product-related archives, correspondence archives, library and access to electronic literature databases

12.3.5

Communication tools, press officer, contact details, Internet access, fax, phone, video conference service

12.3.6

Quality management, determination and assessment of performance indicators, training

12.4

Mandatory tasks and procedures from legislation at regulatory authorities

12.4.1

ADR collection and storing in an electronic database, signal detection and management

12.4.2

Causality assessment and root cause analysis, regular benefit/harm-to-harm/risk assessment

12.4.3

Decision-making processes, monitoring effectiveness of measures taken

12.4.4

Reporting to other competent authorities, international organisations and governments

12.4.5

Quality management system, training

12.4.6

Communication

13

PV Organisation and Public Health

13.1

Detection, documentation and reporting of ADRs on the local level

13.1.1

Reality in rural areas in limited resource settings: patients, diseases, drugs, distributors, HCPs and other health workers

13.1.2

Symptoms of what could be ADRs of drugs used in tropical and other serious infections

13.1.3

What normally happens in the first instance if a patient suffers from such an experience

13.1.4

ADR reporting in industrialised countries on the local level: persons, tools, communication

13.1.5

Industry and drug marketing persons/institutions in ADR reporting in poor and rich settings

13.1.6

Use of e-technology (mobile phones, apps, company websites)

13.2

PV capacity building and organisation on the regional and national level

13.2.1

A national PV policy and legislation

13.2.2

National and regional PV centres and networks; staff, technical equipment, library

13.2.3

System and tools for spontaneous ADR reporting

13.2.4

Concepts for PV capacity building within a centre or health facility, training

13.2.5

Realisation of PV capacity: budget, funds, donors

13.2.6

Co-operation with HCPs, hospitals, professional societies, academia, patient organisations, industry on national and international level

13.3

Public Health Programmes (PHPs) with PV aspects and other PV projects

13.3.1

Major elements of PHPs; WHO as initiator, organiser and co-ordinator of PHPs; co-operation with national regulatory authorities

13.3.2

Tasks and tools related to PV in PHPs: ethnically and socially specific ADRs; CEM, TSR

13.3.3

Important PHPs targeted at AIDS, tuberculosis, malaria: GFATM, BMGF, UNITAID

13.3.4

Vaccination programmes

13.3.5

Other international PV projects: ENCePP, PROTECT, OMOP, MIHARI, ‘Monitoring Medicines’ project

13.3.6

Evaluation of PV data in the context of PHPs

13.4

Co-operative international organisations, industry associations

13.4.1

WHO, WHO Collaborating Centres–Uppsala, Accra, Rabat; ACSoMP, GACVS; CIOMS; regional organisations and initiatives

13.4.2

Patient safety organisations: WAPS, IAPO, EURODIS

13.4.3

International Society of Pharmacovigilance (ISoP), ISPE, IUPHAR

13.4.4

International Conference on Harmonisation (ICH), procedures, deliverables and publications

13.4.5

Mainly pharmaceutical industry: DIA, IFPMA

13.4.6

International Organisation for Standardisation (ISO)

14

Communication

14.1

Context and guidance

14.1.1

Public health goals

14.1.2

Scene and climate

14.1.3

Theories and guidance

14.1.4

Legal framework

14.1.5

Experience on communication effectiveness

14.1.6

Crisis management

14.2

Communication with patients and healthcare professionals: tools, channels and processes

14.2.1

Individual communication

14.2.2

Mass communication

14.2.3

Involvement of the public

14.2.4

Tools and channels

14.2.5

Impact, feedback and evaluation

14.3

Communication with patients and healthcare professionals: contents and presentation

14.3.1

Considering the target population

14.3.2

Typical subject matters and recommendations to patients and healthcare professionals

14.3.3

Selection of data

14.3.4

Information elements and structure of the text

14.3.5

Specific medications and hazards

14.4

Interaction among stakeholders, including the media

14.4.1

Communication for involvement of the public in PV processes

14.4.2

Interactions between stakeholders throughout the communication process

14.4.3

Interaction between stakeholders in relation to RMPs

14.4.4

Specifics for interaction with scientific and general media

14.4.5

Press conferencing

15

Sources of Information

15.1

Primary data: figures, facts, terms, cases

15.1.1

Databases with spontaneous ADR reports

15.1.2

Data from poison control centres: intoxication, contamination

15.1.3

Public health data, epidemiological databases

15.1.4

Sales and exposure data, drug utilisation data

15.1.5

Thesauruses and dictionaries of ADR terms, diseases, drugs

15.2

Secondary information: assessments, judgements, decisions (hardcopy or electronic version)

15.2.1

Study results, ICSR observations, summary assessments

15.2.2

Guidelines, specific recommendations

15.2.3

Drug monographs, regulations, other official decisions

15.2.4

International symposia, local news and advisories

15.2.5

Mixed information, including news, policy, economy, announcements

15.3

Electronic/Internet methods for searching and managing information

15.3.1

Gateways to literature databases

15.3.2

Search engines and attention tools

15.3.3

Software for ADR database searching

15.3.4

Shared networks, discussion groups, chatrooms, weblogs, social media

15.3.5

Services for literature search and drug information management

15.3.6

Strategies for searching for information and literature management

15.4

Materials and training courses, where appropriate, specific for regions or settings

15.4.1

Textbooks

15.4.2

Courses: general or specific methodological (ICSR assessment, signal detection, pharmacoepidemiological studies)

15.4.3

Courses: technical/administrative/procedural topics (e.g. electronic reporting, literature search, PBRERs)

15.4.4

Courses: specific medical topics (e.g. vaccines, anti-HIV drugs, anti-malarials; hepatotoxicity)

15.4.5

‘Hands-on’ practical training

ACSoMP (WHO) Advisory Committee on Safety of Medicinal Products, ADR adverse drug reaction, AE adverse event, AEFI adverse event following immunisation, ATC Anatomical Therapeutic Chemical classification system, BMGF Bill and Melinda Gates Foundation, BRAT Benefit-Risk Assessment Team, CEM cohort event monitoring, CIOMS Council of International Organizations for Medical Sciences, COPD chronic obstructive pulmonary disease, CYP cytochrome P450, DIA Drug Information Association, DSUR Development Safety Update Report, EBGM empirical Bayes geometric mean, EMA European Medicines Agency, ENCePP European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, EURODIS Rare disease patients in Europe, EVMPD EudraVigilance Medicinal Product Dictionary, GACVS Global Advisory Committee on Vaccine Safety, GFATM Global Fund for AIDS, Tuberculosis and Malaria, HCP healthcare professional, HRT hormone replacement therapy, IAPO International Alliance of Patients’ Organizations, IC information component, ICD International Classification of Diseases, ICH International Conference on Harmonization, ICH E2B guideline no. E2B of the International Conference on Harmonisation, ICH M2 guideline no. M2 of the International Conference on Harmonisation, ICSRs individual case safety reports, IDs identification data, IFPMA International Federation of Pharmaceutical Manufacturers and Associations, IMP investigational medicinal products, IMS international medical statistics, INHB incremental net health benefit, ISO International Organisation for Standardisation, ISoP International Society of Pharmacovigilance, ISPE International Society for Pharmacoepidemiology, IUPHAR International Union of Basic and Clinical Pharmacology, LAD large automated health database, LST large simple trial, MAH marketing authorisation holder, MCDA multi-criteria decision analysis, ME medication error, MedDRA Medical Dictionary for Regulatory Activities, MIHARI Medical Information for Risk Assessment Initiative, NNH number needed to harm, NNT number needed to treat, OC oral contraceptive, OMOP Observational Medical Outcomes Partnership, PBRER periodic benefit risk evaluation report, PEM prescription event monitoring, PHPs Public Health Programmes, PIL Patient Information Leaflet, PROTECT Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium, PRR proportional reporting ratio, PSUR periodic safety update report, PV pharmacovigilance, QALY quality-adjusted life year, QPPV qualified person for pharmacovigilance, RCA root cause analysis, REMS risk evaluation and mitigation strategy, RMP risk management plan, ROR reporting odds ratio, SGML Standard Generalised Makeup Language, SMAA stochastic multi-criteria acceptability analysis, SmPC summary of product characteristics, SOP standard operating procedure, SPRT sequential probability ratio test, SQL structured query language, SR spontaneous report, SRS spontaneous reporting system, SSFFC substandard/spurious/falsely labelled/falsified/counterfeit, UMC Uppsala Monitoring Centre, VTE venous thromboembolism, WHO-ART WHO Adverse Reaction Terminology, WHO-DD WHO Drug Dictionary, TSR targeted spontaneous reporting, WAPS World Alliance for Patient Safety, WHO World Health Organization

The practical part consists of 12 times three or four proposals for hands-on exercises. These are related to, and meant to illustrate and provide actual application of, know-how obtained from lectures about those theoretical topics for which skills and experience seem helpful or even necessary. This applies to the fields covered by chapters 4–15. Proposals for practical tasks related to chapters 1–3 are intentionally not included because it was felt that learning of these parts is almost entirely based on the acquirement of theoretical knowledge. The practical part is described in Table 3.
Table 3

List of suggested practical tasks for hands-on exercises as part of the pharmacovigilance curriculum

4P

‘Individual Case Safety Reports’ (‘ICSRs’) - assessment and creation of a report

4P1

Assess an ICSR about a serious AE related to a drug used in a serious disease where co-medication and other risk factors could have contributed and documentation is poor

4P2

Assess an AEFI case report for seriousness, expectedness, correctness of vaccination, risk factors, causality, preventability

4P3

Create an ICSR considering a serious AE related to a herbal medicine: use or design an appropriate form, enter data into fixed fields, write a narrative

5P

Pharmacovigilance in clinical trials: assessment and creation of documents

5P1

Assess the risk-relevant part of a given informed consent form for participants in a large simple trial with respect to relevance, completeness and understandability

5P2

Assess a given DSUR considering a new biotechnological medicine with respect to flaws, gaps and strengths

5P3

Assist a fictitious patient in reporting a serious AE using the recommendation of the Patient Reported Outcomes Safety Event Reporting Consortium (PROSPER)

6P

Counterfeiting, quality defects and medication errors: proposal of analysis and action

6P1

Propose appropriate actions in a poor resource setting scenario where patients unexpectedly did not respond to an antibiotic, and counterfeiting or new bacterial resistance is suspected

6P2

Outline a root cause analysis of a real or fictitious drug-related disaster to which several sequential direct and indirect causes might have contributed

6P3

Create an Ishikawa-Fishbone diagram, a Swiss-Cheese-Barrier diagram or a ‘Management Oversight and Risk Tree’ for the scenario outlined under 6P2

7P

Spontaneous ICSR reporting systems: entering ICSRs into, and retrieval from, the database

7P1

Code an ICSR data using ADR terms and drug thesauruses (MedDRA, WHO-ART, WHO-Drug Dictionary, ICD-10) and appropriate software

7P2

Enter data from an ICSR into an electronic database using the ICH-E2B format and available software

7P3

Retrieve ICSRs from a database with various questions and at different levels of precision and aggregation, using available software

8P

Signal detection and management: finding and analysing remarkable features of a set of ICSRs

8P1

Analyse an ICSR series with respect to a potential signal of a specific new ADR using clinical judgement without statistics

8P2

Analyse an ICSR database for a signal of statistically significant reporting disproportionality of a new ADR by calculating the PRR using available software

8P3

Analyse an ICSR database for a signal of a new reporting trend, drug-drug interaction or a syndrome of several ADRs occurring more often together than would have been predicted from chance

9P

Post-authorisation observational studies

9P1

Appraise a real or fictitious report of a cohort or case-control study. Systematically identify weaknesses according to objective, population, endpoint, bias, confounding, power, statistical tests etc

9P2

Design a case-control study to investigate a suspected relevant difference in the frequencies of a rare serious ADR related to two drugs of the same class. Address risk factors and possible distortions

9P3

Design the set-up of a drug- or disease-related register to monitor ADRs in a given scenario. Address data collection, database structure, data fields, data validation and analysis, potential for record linkage, access and confidentiality

10P

Benefit/risk assessment

10P1

Appraise a published report ‘Benefit/risk assessment of X’. Address the relevance and validity of risk and benefit measures, relation to the target disease, comparability, frequency of manifestation (relative, absolute)

10P2

Assess benefit/risk in a detailed scenario of a common non-serious illness treated by a herbal drug, the efficacy of which has never been shown in a randomised trial but which may cause rare serious ADRs

10P3

Assess benefit/risk in a scenario where a vaccine which causes rare, serious ADRs is clearly effective in preventing a potentially fatal disease, the incidence of which has, however, only been estimated

11P

Pharmacovigilance and risk management systems, risk management plans, inspections

11P1

Assess a real or fictitious RMP with flaws, provided in the context of a marketing authorisation application of a novel promising drug with conceivable but incompletely investigated risks. Define deficits

11P2

Assess a real or fictitious pharmacovigilance system document of a medium-size pharmaceutical company revealing specific deficits of the system. Find the deficits, propose amendments

11P3

Assume the role of a QPPV of a multinational company. You discover that in one country an unfavourable outcome of a phase IV study was concealed. Outline your action, including preparation for inspection

12P

Industry and regulatory authorities, mandatory procedures from legislation

12P1

Consider a range of different AE cases submitted to a multinational company from various sources in several countries. Describe, on the basis of current legislation, how the reports should be handled

12P2

Assess a real or fictitious PBRER with discrepancies between risk-relevant data (single fatality cases, line listing, studies) and the description of benefit/risk and necessary actions. Define deficits and flaws

12P3

Propose, based on detailed information about a newly discovered and confirmed ADR, its description in the SmPC and the patient information leaflet, including the appropriate paragraph(s), and the management of this variation

12P4

Develop an SOP to implement a specific PV procedure, e.g. assessment of an RMP

13P

Pharmacovigilance organisation and public health

13P1

Outline means to stimulate ADR reporting in a resource-limited setting: design a simple-to-handle reporting form with relevant fields and propose technical means to collect and transmit information

13P2

Outline principles and steps to set up a national PV centre in a low-income country. Address personnel, ICSR database and software, communication with patients and HCPs, SOPs

13P3

Design a CEM to monitor ADRs of an anti-infective drug used in the context of a public health programme in a resource-limited country. Discuss relevant elements of the study and methodological alternatives

13P4

Assess, on the basis of an existing performance indicator check list, a real or fictitious PV system

14P

Communication

14P1

Propose a response of the drug authority, in terms of public communication, to a TV report on three cases of a fatal ADR which was not yet confirmed in studies and is not described in the SmPC.

14P2

Propose, based on a detailed scenario of a drug-related problem and on relevant recommendations, a company Direct Healthcare Professional/Provider Communication.

14P3

Design a patient information leaflet for distribution by health professionals, based on a detailed scenario of a drug-related problem in a low-resource, multi-language country with prevalent illiteracy.

14P4

Draft a manuscript for publication of an ADR case or a case series in a scientific journal

15P

Sources of information

15P1

Outline the strategy of a systematic literature review considering a specific ADR of a class of drugs: journals, databases (e.g. PubMed, EMBASE), time window, type of publication

15P2

Put this into action: define a question; select keywords, inclusion and exclusion criteria, keyword combinations; adjust the search according to the actual number of hits and their usefulness

15P3

Conduct an online search for a specific information, e.g. a regulation, guideline, drug monograph, sales figure, disease prevalence, TV recording

15P4

Identify potential sources for funding and develop a grant proposal

ADR adverse drug reaction, AE adverse event, AEFI adverse event following immunisation, CEM cohort event monitoring, DSUR Development Safety Update Report, ICD International Classification of Diseases, ICH International Conference on Harmonization, ICH E2B guideline no. E2B of the ICH, ICSR Individual Case Safety Report, MedDRA Medical Dictionary for Regulatory Activities, PBRER periodic benefit- risk evaluation report, PIL Patient Information Leaflet, PROSPER Patient Reported Outcomes Safety Event Reporting Consortium, PRR proportional reporting ratio, PV pharmacovigilance, QPPV qualified person for pharmacovigilance, RMP Risk Management Plan, SmPC Summary of Product Characteristics, SOP standard operating procedure, WHO-ART WHO Adverse Reaction Terminology

The comprehensive list of references is available in the electronic supplementary material.

4 Discussion

4.1 Contents and Structure of the Curriculum and its Relation to Established Pharmacovigilance Courses

Our curriculum provides comprehensive coverage of almost all areas of PV, i.e. biochemical, clinical, regulatory and methodological aspects. It also addresses issues relevant for highly industralised and low industrialised countries, including their different healthcare structures and issues. Thus, there are topics as heterogeneous as genetic testing, risks related to monoclonal antibodies, adverse events following immunisation (AEFIs), counterfeiting, record linkage, periodic safety update reports and communication to HCPs.

The curriculum as such is neither ready-for-use teaching material nor the description of a course. It just reflects the current status of the rapidly evolving science in PV. Accordingly, it needs continuous updating and, therefore, regular consideration of new or updated information and guidelines is essential. The theoretical part formulates headings and key terms of topics which a trainer should address in order to cover the essential scope of PV, and provides a harmonised structure for the material. It remains up to the lecturer to develop details, texts and slides, real-life cases or scenarios, and other didactic materials. Likewise, the proposals for hands-on exercises are frameworks that would need to be filled with concrete teaching material and explicitly formulated tasks, selected to be of relevance to the audience, e.g. in a particular geographical region. Trainers may find help in the detailed background information provided in the complete reference list. The selected literature (see electronic supplementary material) provides more information than just the basics of PV, and explains in detail most of the important topics.

Even though some of the broad headings of chapters are similar to those of the well-established courses mentioned previously, our curriculum appears to be rather unique in its granularity of key topics, detailed at a three-level hierarchy, for advanced, medium and basic ‘knowledge’ modules, as well as for hands-on exercises. Another advantage of our curriculum resides in its broad and impartial basis of competence through the involvement of many PV experts from international non-governmental not-for-profit organisations which we consider representative for all major fields of PV.

The strict hierarchical and modular structure may seem too rigid to some PV experts; we are well aware of the fact that some people would prefer a different relative weighting of the chapters or sections on their respective level of hierarchy. Others may also criticise the rather homogenous and comprehensive character of the curriculum, arguing that only courses with contents tailored to the interest and need of the specific audience can be useful.

4.2 General Opportunities Offered by the Structure of the Curriculum, and Concrete Options for its Use

Considering these potential criticisms, we believe, however, that they may be counter-balanced by the broad-based and hierarchical structure of the curriculum. This structure allows almost every kind of focusing on specific issues and going into depth as needed, while maintaining the overall context. There are mainly three factors through which this flexibility is achieved:
  1. 1.

    The large number of theoretical modules on different levels of hierarchy and related practical tasks offers an opportunity for the organiser to tailor a course according to the already existing knowledge and experience, as well as the specific situation and need of the trainees and the available time.

     
  2. 2.

    The evenly developed structure of the theoretical part with chapters and sections of about equal length suggests its use in a way that similar periods of time can be allocated to individual units.

     
  3. 3.

    Likewise, the proposed 12 sets of practical tasks are designed in a way that it should be possible to formulate specific exercises which can be fulfilled within approximately equal periods of time.

     

The curriculum can be applied to an intensive course offered over several weeks where a whole day is devoted to each of the 15 theoretical chapters. In this case, the typical four-quarters of a day can easily be allocated to the four sections of every chapter. Also, one day each could additionally be allocated to the proposed 12 sets of exercises, or even to individual practical tasks. At the other end of the options, there may only be an opportunity to give a 1-day course and go over the majority of the contents of the theoretical chapters at a high level within the day, without further delving into the individual sections or even subsections, let alone any inclusion of hands-on training.

Also, there are various opportunities of tailoring a course specifically to the needs of the audience.

For example, the emphasis put on the 15 theoretical chapters and their sections on the one hand, and on the training of practical skills on the other, should be chosen according to the specific training situation. This could be planned in advance or decided upon in specific situations during the actual conduct of a course where a trainer may wish to include some hands-on exercises. These could be expected to enhance active audience participation and to facilitate dialogue and interaction among her- or himself and the course participants.

Using the curriculum for a ‘zooming’ course may be considered on occasion. This would put a specific narrow topic in perspective, i.e. its place within the field of PV. In this case, one would first devote some time for a broad overview of the whole scope of PV on the chapter level, thereafter address a specific chapter with its four sections, and finally focus on one specific section with its set of subsections or even just on a specific subsection, possibly intensified by one or several of the practical tasks.

A further option would be some kind of ‘cluster teaching’, i.e. training in related chapters such as ‘individual case safety reports’ plus ‘spontaneous reporting systems’, ‘signal detection’ plus ‘post-authorisation observational studies’ or ‘communication’ plus ‘sources of information’. Other aspects may specifically apply to the local situation, recent drug regulations, a current safety problem or individual ADR cases reported in the media. These topics might not be part of a standard international curriculum but might be useful supplements as lively illustrations and stimuli for discussion on a case-by-case basis.

4.3 The Way Forward

For some of the theoretical chapters we have started to develop sets of keywords and examples relating to each of the subsections in order to further detail and illustrate their meaning. Such an additional breakdown of the subsections might be considered as the creation of a further level of hierarchy (‘level IV’). Our aim is to complete this work for all 15 chapters. Also, we may add more proposals for practical tasks to choose from. However, such a detailed curriculum would probably be too extensive for publishing in a printed international journal. It is planned, therefore, to make this version available electronically in Drug Safety or on the homepages of WHO and ISoP. An electronic version could be updated relatively easy and as often as necessary in a modular fashion, in line with how PV in scientific, public health and regulatory terms will evolve in the future. Also, online availability would facilitate the use of the curriculum for long-distance courses. An example of a subsection with keywords drawn from an already detailed theoretical chapter is shown in Table 4 to illustrate how it is envisaged the curriculum would look like at the ‘fourth level of hierarchy’.
Table 4

An example of how a subsection of the theoretical chapter 15, with keywords and examples, would look like in the ‘IV levels of hierarchy’ version of the curriculum

15.1.1

Databases with spontaneous ADR reports

UMC: ‘VigiBase’. EMA: ‘EudraVigilance’. Some national PV centres permitting access to anonymised ICSRs, e.g. US FDA, Health Canada, NL Lareb, DE BfArM/PEI. ADR databases of regional PV centres or hospitals for specific users. Problems to get reliable primary information in resource-limited settings

ADR adverse drug reaction, EMA European Medicines Agency, ICSR Individual Case Safety Report, PV pharmacovigilance, UMC Uppsala Monitoring Centre

For any revision of this curriculum in the future and also for the development of the detailed ‘level IV’ version, we would be grateful for comments and suggestions and for feedback from applying the curriculum, as we hope that it will be used by many organisations and trainers and prove helpful for professional capacity building.

Funding

No sources of funding have been received and used for writing this article.

Conflict of interest

Jürgen Beckmann, Ulrich Hagemann, Priya Bahri, Andrew Bate, Ian Boyd, Gerald Dal Pan, Brian Edwards, Ralph Edwards, John McEwen, Kenneth Hartigan-Go, Marie Lindquist, Yola Moride, Sten Olsson, Shanthi Pal, Rachida Soulaymani-Bencheikh, Marco Tuccori, Claudia P. Vaca and Ian C.K. Wong have no conflicts of interest that are directly relevant to the content of this article.

Supplementary material

40264_2014_216_MOESM1_ESM.docx (71 kb)
Supplementary material 1 (DOCX 71 kb)

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Jürgen Beckmann
    • 1
  • Ulrich Hagemann
    • 2
  • Priya Bahri
    • 3
  • Andrew Bate
    • 4
  • Ian W. Boyd
    • 5
  • Gerald J. Dal Pan
    • 6
  • Brian D. Edwards
    • 7
  • I. Ralph Edwards
    • 8
  • Kenneth Hartigan-Go
    • 9
  • Marie Lindquist
    • 8
  • John McEwen
    • 10
  • Yola Moride
    • 11
  • Sten Olsson
    • 8
  • Shanthi N. Pal
    • 12
  • Rachida Soulaymani-Bencheikh
    • 13
  • Marco Tuccori
    • 14
  • Claudia P. Vaca
    • 15
  • Ian C. K. Wong
    • 16
  1. 1.BerlinGermany
  2. 2.BerlinGermany
  3. 3.European Medicines AgencyLondonUK
  4. 4.Pfizer LtdTadworthUK
  5. 5.Ian Boyd ConsultingCanberraAustralia
  6. 6.Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  7. 7.NDA Regulatory Science LtdLeatherheadUK
  8. 8.Uppsala Monitoring CentreUppsalaSweden
  9. 9.Food and Drugs AdministrationDepartment of Health, PhilippinesMuntinlupa CityPhilippines
  10. 10.Discipline of PharmacyUniversity of CanberraCanberraAustralia
  11. 11.Faculty of PharmacyUniversité de MontréalMontrealCanada
  12. 12.Safety and Vigilance, Essential Medicines and Health ProductsWorld Health OrganizationGenevaSwitzerland
  13. 13.Centre Anti Poison et de Pharmacovigilance du MarocRabatMorocco
  14. 14.Hospital of PisaTuscan Regional Centre of PharmacovigilancePisaItaly
  15. 15.Pharmacy SchoolUniversidad Nacional de ColombiaBogotáColombia
  16. 16.Department of Pharmacology and PharmacyLi Ka Shing Faculty of Medicine, University of Hong KongHong KongChina

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