VIII.C.2. Supervision of non-interventional post-authorisation safety studies conducted pursuant to an obligation

Non-interventional PASS conducted pursuant to obligations imposed by a competent authority in the EU (categories 1 and 2 of studies in GVP Module V) are supervised and assessed by the PRAC, unless for PASS requested by a national competent authority of a single Member State according to DIR Art 22a and conducted only in that Member State, where national oversight procedures will apply [DIR Art 107n(1)].

VIII.C.2.1. Roles and responsibilities of the marketing authorisation holder

If the study is a non-interventional study (see VIII.A.), the marketing authorisation holder shall ensure that the study meets the requirements applicable to non-interventional PASS set out in DIR Art 107m–q, REG Art 28b, IR Art 36–38 and this Module. The marketing authorisation holder shall ensure the fulfilment of its pharmacovigilance obligations in relation to the study and that this fulfilment can be audited, inspected and verified (see VIII.B.6. and VIII.B.7.).

Following the imposing as a condition to the marketing authorisation to conduct a non-interventional PASS, the marketing authorisation holder shall develop a study protocol and submit it to the national competent authority or the PRAC for review [DIR Art 107n(1)] as appropriate. The marketing authorisation holder has the responsibility to ensure that the study is not a clinical trial, in which case Directive 2001/20/EC and Volume 10 of The Rules Governing Medicinal Products in the European Union (11) shall apply.

The study may commence only when the written endorsement from the national competent authority or the PRAC, as appropriate, has been issued. When a letter of endorsement has been issued by the PRAC, the marketing authorisation holder shall forward the protocol to the national competent authority of the Member State(s) in which the study is to be conducted and may thereafter commence the study according to the endorsed protocol [DIR Art 107n(3)]. EU and national requirements shall be followed to ensure the well-being and rights of participants in the study [DIR Art 107m(2)].

Prior to submission of the protocol, the marketing authorisation holder may submit a request to the national competent authority or the Agency, as appropriate, for a pre-submission meeting (with the Agency and the PRAC rapporteur in case the request is submitted to the Agency) in order to clarify specific aspects of the requested study (such as study objectives, study population, definition of exposure and outcomes) and to facilitate the development of the protocol in accordance with the objectives determined by the national competent authority or the PRAC.

After a non-interventional imposed PASS has been commenced, the marketing authorisation holder shall submit any substantial amendments to the protocol, before their implementation, to the national competent authority or to the PRAC, as appropriate [DIR Art 107o] (see VIII.A.1. for the definition of a substantial amendment).

Upon completion of the study, the marketing authorisation holder shall submit a final study report, including a public abstract, to the national competent authority or to the PRAC as soon as possible and not later than 12 months after the end of data collection, unless a written waiver has been granted by the national competent authority or the PRAC, as appropriate [DIR Art 107p(1)]. When the PRAC is responsible for supervision of the PASS, the marketing authorisation holder should request the waiver in writing to the Agency at least three months before the due date for the submission of the report. The request should include a justification for the waiver. The request should be assessed by the PRAC rapporteur and granted or rejected by the PRAC on the basis of the justification and timeline submitted by the marketing authorisation holder.

The marketing authorisation holder shall submit the study protocol, the abstract of the final study report and the final study report in English except for studies to be conducted in only one Member State that requests the study according to DIR Art 22a. For the latter studies, the marketing authorisation holder shall provide an English translation of the title and abstract of the study protocol as well as an English translation of the abstract of the final study report [IR Art 36].

VIII.C.2.2. Roles and responsibilities of the PRAC and the national competent authority

Within 60 days from submission of the draft protocol, the national competent authority or the PRAC, as appropriate, shall issue a letter endorsing the draft protocol, a letter of objection or a letter notifying the marketing authorisation holder that the study is a clinical trial falling under the scope of Directive 2001/20/EC. The letter of objection shall set out in detail the grounds for the objection in any of the following cases:

• it is considered that the conduct of the study promotes the use of a medicinal product;
• it is considered that the design of the study does not fulfil the study objectives [DIR Art 107n(2)].

If the study proves to be interventional, the PRAC or the national competent authority as applicable should issue an explanatory statement to the marketing authorisation holder that the study is a clinical trial falling under the scope of Directive 2001/20/EC.

When the PRAC is involved in the oversight of the study, the PRAC will nominate a PRAC rapporteur responsible for the supervision of the PASS. The PRAC rapporteur should draft a protocol assessment report and submit it for review and approval by the PRAC.

In case of submission of an amended study protocol, the national competent authority or the PRAC, as appropriate, shall assess the amendments and inform the marketing authorisation holder of its endorsement or objection [DIR Art 107o]. The national competent authority or the PRAC will provide the marketing authorisation holder with a letter of endorsement or objection to the protocol amendment within 60 days of submission. The letter of objection will provide a timeline by which the marketing authorisation holder should resubmit an amended version of the protocol.

Where the study protocol is assessed by a national competent authority, this national competent authority should share its assessment with the other concerned Member States where the product is authorised.

Concerning the assessment of study results, in cases where the PRAC is involved in the oversight of the study, the PRAC will produce an assessment report and issue a recommendation that will be addressed to the CHMP or CMDh, as applicable.

VIII.C.2.3. Roles and responsibilities of the Agency

The Agency shall provide scientific secretariat to the PRAC.

The Agency will inform the marketing authorisation holder in writing and within the appropriate timelines of the decisions of the PRAC with respect to the assessment of the following:

• study protocol;
• study protocol amendments;
• final study report;
• waiver request for the submission of the final study report.

When the marketing authorisation holder submits a request to the Agency for a pre-submission meeting, the Agency will be responsible for a timely set up of the meeting with the Agency and the PRAC rapporteur.

The Agency shall make public on the European medicines web-portal protocols and public abstracts of results of the post-authorisation safety studies referred to in DIR Art 107n and 107p.