VIII.A Introduction

Regulation (EC) No 726/2004, Directive 2001/83/EC and Commission Implementing Regulation (EU) No 520/2012 (hereinafter referred to as REG, DIR and IR) include provisions for post-authorisation safety studies applicable in the European Union (EU).

A post-authorisation safety study (PASS) is defined in DIR Art 1(15) as any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.

A PASS may be interventional or non-interventional. This Module concerns both interventional and non-interventional PASS, with a main focus on non-interventional ones. It does not concern pre-clinical safety studies. Non-interventional PASS concerned by this guidance are those initiated, managed or financed by a marketing authorisation holder voluntarily or pursuant to an obligation imposed by an EU competent authority [DIR Art 107m(1), REG Art 28b].

Non-interventional PASS concerned can be:

• imposed as an obligation in accordance with REG Art 9(4)(cb) and Art 10a(1)(a) and with DIR Art 21a(b) and Art 22a(1)(a) (category 1 of studies in GVP Module V);
• imposed as a specific obligation in the framework of a marketing authorisation granted under exceptional circumstances (category 2 of studies in GVP Module V);
• required in the risk management plan (RMP) to investigate a safety concern or to evaluate the effectiveness of risk minimisation activities (category 3 of studies in GVP Module V); or
• conducted voluntarily by a marketing authorisation holder.

Non-interventional PASS shall be conducted in accordance with the following provisions:

• DIR Art 107m for non-interventional PASS initiated, managed or financed by a marketing authorisation holder voluntarily or pursuant to imposed obligations;
• DIR Art 107n–q, REG Art 28b and IR Art 36–38 for non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority (categories 1 and 2 of studies in GVP Module V).

A PASS is non-interventional if the following requirements are cumulatively fulfilled (see Volume 10 of The Rules Governing Medicinal Products in the European Union, Questions and Answers, Version 11.0, 15 May 2013, Question 1.10):

• the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation;
• the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and
• no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data.

Non-interventional studies are defined by the methodological approach used and not by its scientific objectives. Non-interventional studies include database research or review of records where all the events of interest have already happened (this may include case-control, cross-sectional, cohort or other study designs making secondary use of data). Non-interventional studies also include those involving primary data collection (e.g. prospective observational studies and registries in which the data collected derive from routine clinical care), provided that the conditions set out above are met. In these studies, interviews, questionnaires, blood samples and patient follow-up may be performed as part of normal clinical practice.

If a PASS is interventional, the provisions of Directive 2001/20/EC and of Volume 10 of The Rules Governing Medicinal Products in the European Union shall apply.

The purposes of this Module are to:

• provide general guidance for the transparency, scientific standards and quality standards of noninterventional PASS conducted voluntarily or pursuant to an obligation imposed by an EU competent authority (VIII.B.);
• describe procedures whereby an EU competent authority may impose on a marketing authorisation holder an obligation to conduct a PASS (VIII.C.1.);
• describe procedures that apply to non-interventional PASS pursuant to an obligation imposed by an EU competent authority for the protocol oversight and reporting of results (VIII.C.2.) and for subsequent changes to the marketing authorisation (VIII.C.3.).

Legal requirements are identifiable by the modal verb “shall”. Recommendations that are not legal requirements are provided using the modal verb “should”. National and Union requirements for ensuring the well-being and rights of participants in non-interventional PASS shall also apply [DIR Art 107m(2)].

In VIII.B., some legal requirements which are mandatory to non-interventional PASS conducted pursuant to an obligation imposed by an EU competent authority are recommended for noninterventional PASS conducted voluntarily in order to support the same level of transparency, scientific standards and quality standards. This applies, for example, to the format and content of the study protocol and of the final study report and its abstract.

For non-interventional PASS, this guidance applies to studies that involve primary collection of safety data directly from patients and healthcare professionals as well as those that make secondary use of data previously collected from patients and healthcare professionals for another purpose.