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Post-authorisation non-interventional safety studies

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Post-Authorisation Safety Study (PASS) may be interventional (clinical trial) or non-interventional.

Non-interventional safety study does not interfere with the treatment or medical observation (data are collected within normal clinical practice). The PASS can be imposed as obligation or conducted voluntarily by a marketing authorisation holder.

Conduction of a non-interventional safety study may be imposed by State Agency of Medicines or Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) to fulfil the specific obligations in the framework of a marketing authorisation (i.e. granted under exceptional circumstances) during or after granting the marketing authorisation (see Imposed non-interventional safety study).

Objectives of the non-interventional safety study:

  • to quantify potential or identified risks;
  • to provide evidence about the absence of risks;
  • to evaluate the risks 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);
  • assess patterns of drug utilisation that add knowledge regarding the safety of the medicinal product (e.g. collection of information on indication, dosage, co-medication, medication errors);
  • to measure the effectiveness of a risk management measures.

Criteria of the non-interventional safety study are as follows:

  • 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;
  • no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data (i.e. retrospective studies: case-control study, cohort study, etc. and prospective studies).

Non-interventional safety study shall be conducted in accordance with the Commission Implementing Regulation (EU) No 520/2012, Medicinal Products Act and Good Pharmacovigilance Practices.

Imposed non-interventional safety study

Conduction of a non-interventional safety study is usually imposed by PRAC. In this case PRAC will assess the study protocol and study results – see guidance on EMA website

In case the non-interventional safety study is imposed by the State Agency of Medicines, the study protocol and final report should be sent to State Agency of Medicines’ e-mail PASS@ravimiamet.ee for approval.

Approval of the study in Estonia

The following documents should be presented to State Agency of Medicines for approval of the study:

  • Digitally signed application (confirming that the study is a PASS and that the study will be conducted only in Estonia)
  • Study protocol (according to GVP Module VIII B. 5.1)
  • Approval of the Medical Ethics Committee (can be submitted later than application but prior to the start of the study)
  • List of investigators (recommendable).

State Agency of Medicines notifies the applicant about the approval of the study within 60 days after the submission of study protocol.

Amendment of the study protocol

For the amendment of the study protocol the marketing authorisation holder must submit essential amendments to the protocol to the State Agency of Medicines (or to PRAC) for approval. The State Agency of Medicines (or the PRAC) will inform the marketing authorisation holder of the approval of or refusal to approve the amendments within 30 days. In case the approval was given by the PRAC, the marketing authorisation holder must prior the implementation of the amendments submit the approval of the PRAC to the State Agency of Medicines.

Final study report

Within 12 months after the completion of the study, the marketing authorisation holder must electronically submit to the State Agency of Medicines the final study report (according to the GVP VIII B. 5.3.2.), including the date of the electronic registration (EU PAS/ENCePP E- Register) of the study.

Registration of the non-interventional safety study in the EU PAS/ENCePP E- register

Marketing authorisation holder must enter the following data into EU PAS/ENCePP E- register:

  • Study protocol;
  • Amendments to the study protocol within 2 weeks after the approval;
  • Interim reports and final reports.

Notification requirements in Estonia prior to the start of the study

Before commencement of the study in Estonia, the approval of the medical ethics committee is required. State Agency of Medicines shall be notified by sending to the e-mail address PASS@ravimiamet.ee the data on planned start of the study, approval from the Medical Ethics Committee and study report approved by the Medical Ethics Committee.

Inclusion of the non-interventional study in the Risk Management Plan (RMP) and presentation of the data in the Periodic Safety Update report (PSUR)

Imposed non-interventional study should be included in all relevant sections of the RMP. Study protocol should be provided in the RMP (Annex 6). (See GVP Module V)

Results of the PASS study should be presented in relevant sections of the PSUR. (See GVP Module VII).

If an important safety concern (including safety signal) has been identified in the course of a study, the marketing authorisation holder should inform the State Agency of Medicines and other Member States immediately.

Further information about post-authorisation non-interventional safety studies can be obtained from:
e-mail: PASS@ravimiamet.ee

Phone: + 372 737 4140. dr Maia Uusküla

See also

Medicinal Products Act

Questions and answers on practical transitional measures for the implementation of the pharmacovigilance legislation

Directive 2001/83/EC of the European Parliament and of the Council 2001/83/EC

Commission Implementing Regulation (EU) No 520/2012

Regulation (EC) No 726/2004 of the European Parliament and of the Council 726/2004

GVP Module VIII – Post-authorisation safety studies

GVP Module V - Risk management systems

GVP Module VII – Periodic safety update report)