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ENCePP Guide on Methodological Standards in Pharmacoepidemiology


9. Data protection and ethical aspects

9.1. Patient and data protection


In Europe, both EU and national legislation determines what is acceptable with regards to patient data access, data linkage and consent issues, including domains such as human rights and duty of confidentiality. Therefore, while individual data custodians may have differing requirements related to what approvals are needed before data can be released, studies conducted in Europe must meet all applicable EU and national legislation.


The provisions of the legislation on the protection of individuals with regard to the processing of personal data and on free movement of such data, as laid down in Directive 95/46/EC and Regulation (EC) No 45/2001 of the European Parliament and of the Council, need to be followed in the EU. For interventional research, the Directive 2001/20/EC and the Guidelines for Good Clinical Practice (Commission Directive 2005/28/EC) apply.  Directive 2001/20 EC will be repealed on the day of entry into application of the new Clinical Trials Regulation (Regulation (EU) No 536/2014). In addition, marketing authorisation holders (MAHs) and investigators must follow relevant national legislation and guidance of those Member States where the study is being conducted (Directive 2001/83/EC and Directive 95/46/EC).


Article 36 of the Commission Implementing Regulation (EU) No. 520/2012 specifies that for post-authorisation safety studies (PASS) imposed as an obligation, MAHs shall ensure that all study information is handled and stored in a way that ensure the confidentiality of the study records. The GVP Module VIII - Post-authorisation safety studies recommends that these provisions should also be applied to PASS voluntarily initiated, managed or financed by a MAH.


The ISPE Good pharmacoepidemiology practice provides recommendations on the protection of human subjects and refers to the ISPE guidelines on Data Privacy, Medical Record Confidentiality, and Research in the Interest of Public Health. It also recommends that the plans for protecting human subjects should be described in a stand-alone section of the study protocol.


9.2.Scientific integrity and ethical conduct


Principles of scientific integrity and ethical conduct are paramount in any medical research. The Declaration of Helsinki provides ethical principles addressed primarily to physicians involved in medical research involving human subjects, including research on identifiable human material and data. The ENCePP Code of Conduct offers standards for scientific independence and transparency of research in pharmacoepidemiology and pharmacovigilance. To this end, the Code of conduct promotes best practice for the interactions between investigators and study funders in critical areas such as planning, conduct and reporting of studies. As a core transparency measure, it recommends that the protocols of all pharmacoepidemiology and pharmacovigilance studies should be registered in the EU PAS Register, ideally before they start, and study findings published irrespective of positive or negative results, to avoid publication bias.


Guided by three core values (best science, strengthening public health, transparency), the ADVANCE Code of Conduct for Collaborative Vaccine Studies (Vaccine 2017;35(15):1844-55) includes 45 recommendations across 10 topics (Scientific integrity, Scientific independence, Transparency, Conflicts of interest, Study protocol, Study report, Publication, Subject privacy, Sharing of study data, Research contract). Each topic includes a definition, a set of recommendations and a list of additional reading. The concept of the study team is introduced as a key component of the ADVANCE Code of Conduct with a core set of roles and responsibilities. It also provides direct access to a comprehensive list of relevant guidelines. The Good Pharmacoepidemiology Practices (GPP) of the International Society for Pharmacoepidemiology (ISPE) proposes practices and procedures that should be considered to help ensure the quality and integrity of pharmacoepidemiological research, including detailed guidance for protocol development, roles and responsibilities, study conduct, communication, reporting of adverse events and archiving. The Good Epidemiology Practice (GEP) of the International Epidemiological Association addresses four general ethical principles for research (Autonomy, Beneficence, Non-maleficence and Justice) and proposes rules for good research behaviour in relation to working with personal data, data documentation, publication, the exercise of judgment and scientific misconduct.


The CIOMS International Ethical Guidelines for Health-related Research Involving Humans (Geneva: 2016) provides international vetted ethical principles and detailed commentary on how universal ethical principles should be applied, with particular attention to conducting research in low-resource settings. It includes 25 guidelines addressing different topics, settings and population groups concerned by health-related research.


The Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in Medical Journals by the International Committee of Medical Journal Editors (ICJME) include clear statements on ethical principles related to publication in biomedical journals. Authorship and contributorship, editorship, peer review, conflicts of interest, privacy and confidentiality and protection of human subjects and animals in research are addressed.

The Agency for Healthcare Research and Quality (AHRQ) published Registries to Evaluate Patient Outcomes: a User’s guide, Third Edition, 2014, which is a reference for establishing, maintaining and evaluating the success of registries created to collect data about patient outcomes. Section II: ‘Legal and Ethical Considerations for Registries’ is a specific chapter dedicated to ethics, data ownership, and privacy. The concepts within are useful although focused on US law.



Individual Chapters:


1. Introduction

2. Formulating the research question

3. Development of the study protocol

4. Approaches to data collection

4.1. Primary data collection

4.1.1. Surveys

4.1.2. Randomised clinical trials

4.2. Secondary data collection

4.3. Patient registries

4.3.1. Definition

4.3.2. Conceptual differences between a registry and a study

4.3.3. Methodological guidance

4.3.4. Registries which capture special populations

4.3.5. Disease registries in regulatory practice and health technology assessment

4.4. Spontaneous report database

4.5. Social media and electronic devices

4.6. Research networks

4.6.1. General considerations

4.6.2. Models of studies using multiple data sources

4.6.3. Challenges of different models

5. Study design and methods

5.1. Definition and validation of drug exposure, outcomes and covariates

5.1.1. Assessment of exposure

5.1.2. Assessment of outcomes

5.1.3. Assessment of covariates

5.1.4. Validation

5.2. Bias and confounding

5.2.1. Selection bias

5.2.2. Information bias

5.2.3. Confounding

5.3. Methods to handle bias and confounding

5.3.1. New-user designs

5.3.2. Case-only designs

5.3.3. Disease risk scores

5.3.4. Propensity scores

5.3.5. Instrumental variables

5.3.6. Prior event rate ratios

5.3.7. Handling time-dependent confounding in the analysis

5.4. Effect measure modification and interaction

5.5. Ecological analyses and case-population studies

5.6. Pragmatic trials and large simple trials

5.6.1. Pragmatic trials

5.6.2. Large simple trials

5.6.3. Randomised database studies

5.7. Systematic reviews and meta-analysis

5.8. Signal detection methodology and application

6. The statistical analysis plan

6.1. General considerations

6.2. Statistical analysis plan structure

6.3. Handling of missing data

7. Quality management

8. Dissemination and reporting

8.1. Principles of communication

8.2. Communication of study results

9. Data protection and ethical aspects

9.1. Patient and data protection

9.2. Scientific integrity and ethical conduct

10. Specific topics

10.1. Comparative effectiveness research

10.1.1. Introduction

10.1.2. General aspects

10.1.3. Prominent issues in CER

10.2. Vaccine safety and effectiveness

10.2.1. Vaccine safety

10.2.2. Vaccine effectiveness

10.3. Design and analysis of pharmacogenetic studies

10.3.1. Introduction

10.3.2. Identification of generic variants

10.3.3. Study designs

10.3.4. Data collection

10.3.5. Data analysis

10.3.6. Reporting

10.3.7. Clinical practice guidelines

10.3.8. Resources

Annex 1. Guidance on conducting systematic revies and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes