1. Post-Authorisation Safety Studies (PASS)

1. Scope of a Post-Authorisation Safety Study (PASS)

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A Post-Authorisation Safety Study (PASS) is a study that is conducted after a medicine has been authorised. It serves to obtain further information on a medicine's safety and benefit-risk profile, or to evaluate the effectiveness of risk-management measures (see also Directive 2001/83/EC, Art. 1(15)) and support regulatory decision-making. The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols of imposed PASSs (see also 1.4) and for assessing their results.

2. Aims of a Post-Authorisation Safety Study (PASS)

The main aims for initiating a PASS should include 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, 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);

• to evaluate the risks of a medicinal product after long-term use;

• to provide evidence about the absence of risks;

• to assess patterns of medicines utilisation that add knowledge regarding its safety or appropriateness of risk management measures (e.g. information on indication, off-label use, dosage, co-medication or medication errors in clinical practice);

3. Categorising PASS

PASSs can either be clinical trials (interventional) or non-interventional studies. 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 the definition (see above) in Directive 2001/83/EC Art 1(15).

Interventional PASS are clinical trials and must follow the regulation (EU) No 536/2014 (Directive 2001/20/EC until REG536/2014 becomes applicable).

Non-interventional PASS should cumulatively fulfil the following requirements (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)[1]:

• 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.

In essence, non-interventional PASSs are defined by the methodological approach used and not by their scientific objectives and may for example:

• 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 (these study types are explained in Course 2 Lesson 1), or a systematic literature review or a meta-analysis depending on its aim)

• also include primary data collection (e.g., prospective observational studies and registries in which the data collected derive from routine clinical care). In these studies, interviews, questionnaires, blood samples and patient follow-up may be performed as part of normal clinical practice.

• follow pharmacoepidemiologic approaches (designs) such as

4. Initiation of a PASS

PASSs are either imposed by regulatory authorities or voluntarily initiated by MAHs.

Imposed PASSs can in the EU be requested by the EMA (the PRAC) or the respective national competent authority (NCA) during the evaluation of the initial marketing authorisation application or during the post-authorisation phase, whenever there are concerns about the risks of an authorised medicinal product for which a PASS might significantly impact the risk-benefit profile of the product. Marketing-authorisation holders (MAHs) are obliged to sponsor or conduct imposed PASSs.

A request for a PASS will be issued under the following conditions:

• as part of the initial marketing authorisation application. A marketing authorisation may be granted under the condition that a PASS is being conducted if during the evaluation of a marketing authorisation application the need for a PASS is identified leading to a conditional marketing authorisation or under exceptional circumstances.
• during a post- authorisation regulatory procedure. The need for a PASS could be identified by the EMA or an NCA during a post- authorisation regulatory procedure, for example, an extension or a variation to a marketing authorisation, a renewal procedure or a periodic safety update (PSUR) procedure.
• due to an emerging safety concern. After the granting of the marketing authorisation, the EMA or NCA may impose an obligation to conduct a PASS if there are concerns about the risk of the authorised medicinal product.

Voluntary PASSs are sponsored or conducted by MAHs on their own initiative. They include non-imposed studies that are 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 Good Pharmacovigilance Practices (GVP) Module V).

For more detailed information read here:

EMA: Post-authorisation safety studies (PASS)
https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/post-authorisation-safety-studies-pass-0

Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 3) 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-studies-rev-3_en.pdf