Non-interventional studies (NIS) within the European Union are governed through national legislation, unless the study is a non-interventional post-authorisation safety study (PASS) that has been imposed as a condition of a marketing authorisation.  In which case, the requirements of Regulation EC/726/2004 [1] and Directive 2001/83/EC [2] apply…AS WELL AS…the national legal requirements.

Regulation EC/726/2004 and Directive 2001/83/EC provide the framework for regulatory authorities to imposed and govern non-interventional post-authorisation safety study (PASS) and provide details on the requirements manufacturing authorisation holders need to comply with when conducting imposed PASS. Additionally, Article 108a of Directive 2001/83/EC required the EMA…draw up:

1. 1. Guidance on good pharmacovigilance practices (GVPs) for both competent authorities and marketing authorisation holders [3]
   2. Scientific guidance on post-authorisation efficacy studies [4]

Meaning?  These guidance documents (GVPs) are supplemental to Regulation EC/7262004 and Directive 2001/83/EC.

According to the EMA, good pharmacovigilance practices (GVPs) are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU). GVP apply to marketing-authorisation holders, the European Medicines Agency (EMA) and medicines regulatory authorities in EU Member States. They cover medicines authorised centrally via the Agency as well as medicines authorised at national level [3].

Which GVPs are Applicable to the Conduct of Non-Interventional Studies?

We are intentionally focusing on the GVPs that are applicable to the conduct of non-interventional studies i.e., those that guide the regulatory requirements, design, conduct and reporting of NIS. Based on this, the 3 (three) key GVPs are:

• • GVP Module V = PASS Categories (refer to Section V.B.6.3) [5]
  • GVP Module VI = Safety Reporting Requirements for Non-Interventional Studies (refer to Section VI.C.1.2) [6]
  • GVP Module VIII = Guidelines on Post-Authorisation Safety Studies (PASS) [7]

Below, we explore these good pharmacovigilance practices (GVPs) in more detail…

PASS Categories – GVP Module V

Understanding the categorises of non-interventional post-authorisation safety studies (see below) is important because this drives the regulatory requirements for your studies.  For example, mandated PASS (Class I and II) will require PRAC endorsement of the protocol (for centrally authorised products), which must use the PASS protocol template etc. 

The GVPs are interconnected in that GVP module V provides you with the PASS categories.  Imposed PASS must comply with the requirements stipulated in Articles 107m – 107q of Directive 2001/83/EC and the requirements of GVP module VIII…and the safety reporting requirements of GVP module VI.

Safety Reporting Requirements for Non-Interventional Studies – GVP Module VI

According to Directive 2001/83/EC (Article 107.3), marketing authorisation holders are required to submit information on all serious suspected adverse reactions that occur in the Union and in third countries within 15 days following the day on which the marketing authorisation holder concerned gained knowledge of the event.  Furthermore, information on all non-serious suspected adverse reactions that occur in the Union, should be submitted within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event.

GVP Module VI provides further detail and guidance on the expectations for the management of safety reporting from non-interventional post-authorisation studies (as per Section VI.C.1.2).  Specifically, non-interventional post-authorisation studies should be distinguished between: 

• • Studies with a design based on primary data collection directly from healthcare professionals or consumers (i.e. where the events of interest are collected as they occur specifically for the study), and
  • Studies with a design based on secondary use of data (i.e. where the events of interest have already occurred and have been collected for another purpose).

For combined studies with a design based on both primary data collection and secondary use of data, the submission of ICSRs is required exclusively for the data obtained through primary data collection and the guidance provided in Section VI.C.1.2.1.1 of GVP module VI. should be followed. For the events identified through secondary use of data, the guidance in Section VI.C.1.2.1.2 applies. All adverse events/reactions collected as part of this type of studies should be recorded and summarised in the interim safety analysis and in the final study report.

Details on the requirements for the management of adverse events for non-interventional post-authorisation studies with a design based on primary data collection are summarised in Table VI.1 (VI.C.1.2.1.1) of GVP module VI (see below).

Non-interventional post-authorisation studies with a design based on secondary use of data:  The design of such studies is characterised by secondary use of data previously collected from consumers or healthcare professionals for other purposes. Examples include medical chart reviews (including following-up on data with healthcare professionals), analysis of electronic healthcare records, systematic reviews, meta-analyses (as per Section VI.C.1.2.1.2 of GVP Module VI) [6].

For these studies, the submission of suspected adverse reactions in the form of ICSRs is not required. All adverse events/reactions collected for the study should be recorded and summarised in the interim safety analysis and in the final study report unless the protocol provides for different reporting with a due justification (as per Section VI.C.1.2.1.2 of GVP Module VI) [6].

Post-Authorisation Safety Studies (PASS) – GVP Module VIII

GVP Module VIII provides detailed guidance on all aspects related to the design, registration, conduct and reporting of non-interventional PASS [7].

According to GVP Module VIII, 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 (as per Section VIII.B.1 of GVP Module VIII) [7]:

• • ENCePP Guide on Methodological Standards in Pharmacoepidemiology
  • ENCePP Checklist for Study Protocols
  • Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population
  • Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP)

GVP Module VIII, also provides guidance on:

• • Study registration
  • Study protocol
  • Format and content of the study protocol
  • Substantial amendments to the study protocol
  • Reporting of pharmacovigilance data to competent authorities
  • Data relevant to the risk-benefit balance of the product
  • Reporting of adverse reactions/adverse events
  • Study reports
  • Progress report and interim report of study results
  • Final study report
  • Publication of study results
  • Submission of manuscripts accepted for publication
  • Data protection
  • Quality systems, audits and inspections
  • Impact on the risk management system 

References

1. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing a European Medicines Agency

Link: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02004R0726-20220128 

2. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use

Link: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02001L0083-20190726#tocId1 

3. EMA – Good Pharmacovigilance Practices

Link: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/good-pharmacovigilance-practices 

4. EMA – Scientific Guidance on Post-Authorisation Efficacy Studies

Link: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/post-authorisation-efficacy-studies-questions-answers 

5. GVP Module V – Risk management systems (Rev 2)

Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf 

6. GVP Module VI – Collection, management and submission of reports of suspected

adverse reactions to medicinal products (Rev 2)

Link: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf 

7. GVP Module VIII – Post-authorisation safety studies (Rev 3)

Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-studies-rev-3_en.pdf 

Useful Resources

McCully S. Regulatory considerations for real-world research studies in Europe. https://www.raps.org/news-and-articles/news-articles/2021/7/regulatory-considerations-for-real-world-research. Regulatory Focus. Published online 28 July 2021

Link: https://www.raps.org/news-and-articles/news-articles/2021/7/regulatory-considerations-for-real-world-research?feed=Regulatory-Focus