VIII.B.1. Principles

In the light of DIR Art 1(15), a post-authorisation study should be classified as a post-authorisation safety study when the main aim for initiating the study includes any of the following objectives:

• to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another medicinal product or class of medicinal products as appropriate, and investigate risk factors, including effect modifiers;
• to evaluate the risks of a medicinal product used in a patient population for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment or other relevant comorbidity or co-medication);
• to evaluate the risks of a medicinal product after long-term use;
• to provide evidence about the absence of risks;
• to assess patterns of drug utilisation that add knowledge regarding the safety of the medicinal product or the effectiveness of a risk management measure (e.g. collection of information on indication, off-label use, dosage, co-medication or medication errors in clinical practice that may influence safety, as well as studies that provide an estimate of the public health impact of any safety concern);
• to measure the effectiveness of a risk management measures.

Whereas the PASS design should be appropriate to address the study objective(s), the classification of a post-authorisation study as a PASS is not constrained by the type of design chosen if it fulfils the criteria as set in DIR Art 1(15). For example, a systematic literature review or a meta-analysis may be considered as PASS depending on its aim.

Relevant scientific guidance should be considered by marketing authorisation holders and investigators for the development of study protocols, the conduct of studies and the writing of study reports, and by the Pharmacovigilance Risk Assessment Committee (PRAC) and national competent authorities for the evaluation of study protocols and study reports. Relevant scientific guidance includes, amongst others, the ENCePP Guide on Methodological Standards in Pharmacoepidemiology (3) , the ENCePP Checklist for Study Protocols (4) , the Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population (5) , and the Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP) (6) .

For studies that are funded by a marketing authorisation holder, including studies developed, conducted or analysed fully or partially by investigators who are not employees of the marketing authorisation holder, the marketing authorisation holder should ensure that the investigators are qualified by education, training and experience to perform their tasks. The research contract between the marketing authorisation holder and investigators should ensure that the study meets its regulatory obligations while permitting their scientific expertise to be exercised throughout the research process. In the research contract, the marketing authorisation holder should consider the provisions of the ENCePP Code of Conduct (7) , and address the following aspects:

• rationale, main objectives and brief description of the intended methods of the research to be carried out by the investigator(s);
• rights and obligations of the investigator(s) and marketing authorisation holder;
• clear assignment of tasks and responsibilities;
• procedure for achieving agreement on the study protocol;
• provisions for meeting the marketing authorisation holder’s pharmacovigilance obligations, including the reporting of adverse reactions and other safety data by investigators, where applicable;
• intellectual property rights arising from the study and access to study data;
• storage and availability of analytical dataset and statistical programmes for audit and inspection;
• communication strategy for the scheduled progress and final reports;
• publication strategy of interim and final results.

Non-interventional post-authorisation safety studies shall not be performed where the act of conducting the study promotes the use of a medicinal product [DIR Art 107m(3)]. This requirement applies to all studies and to all activities performed in the study, including for studies conducted by the personnel of the marketing authorisation holder and by third parties on behalf of the marketing authorisation holder.

Payments to healthcare professionals for participating shall be restricted to compensation for time and expenses incurred [DIR Art 107m(4)].