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RWR Insights | EU – Applicability of GVPs to the Conduct of Non-Interventional Studies

RWR CONTEXT

The EMAs Good Pharmacovigilance Practice guidelines (GVPs) supplement the requirements of Directive 2001/83/EC (Article 107m – 107q)  for non-interventional studies and provide additional detailed guidance on (1) the classification of non-interventional post-authorisation safety studies (PASS) (GVP Module V), (2) guidance on the design, registration, conduct and reporting of non-interventional PASS (GVP Module VIII), and (3) safety reporting requirements for non-interventional studies (GVP Module VI).

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. 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 

RWR Insights | EU – Applicability of GVPs to the Conduct of Non-Interventional Studies2022-08-07T16:22:44+00:00

RWR Insights – What GxPs are Applicable to Non-Interventional (Observational) Studies?

RWR CONTEXT

In this series of ‘RWR Insights’ we lay out what GxPs are globally applicable to observational studies with the aim of providing you confidence that you know what is applicable and what you need to consider and/or comply with.

With knowledge comes understanding…with understanding comes confidence…

A question we are commonly asked is “what GxPs are applicable to non-interventional (observational) studies?”.  The concern that researchers often have is that they should be following GCP but are struggling to do so because many of the elements, such as the Investigator’s Brochure (IB), IMP accountability, drug labelling etc, are not applicable when conducting observational studies.  That being the case, what should you follow (comply with), and more to the point what are you missing?  Is there something you should be complying with that you aren’t?

In this series of ‘RWR Insights’ we lay out what GxPs are globally applicable to observational studies with the aim of providing you confidence that you know what is applicable and what you need to consider and/or comply with.

With knowledge comes understanding…with understanding comes confidence…

Is GCP Applicable to Observational Studies?

Short Answer = No (see details below)

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting clinical TRIALS that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of TRIAL subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the CLINICAL TRIAL data are credible (as per the Introduction to ICH E6(R2)) [ref 1].

Observational studies are not clinical trials (see USA examples below):

What is Industry Best Practice When Conducting Observational Studies?

Industry Best Practice =  Conduct the study in accordance with the principles of Good Pharmacoepidemiologic Practices (GPP) [ref 5], the Declaration of Helsinki [ref 6] and in compliance with the applicable national laws and guidelines (see details below).

ISPE Guidelines for Good Pharmacoepidemiology Practices (GPP)

    • ISPE GPP [ref 5] was initially issued in 1996 (the same year as ICH GCP; ref 1) and last revised in 2015
    • ISPE GPP is made up of seven (7) sections
    • Two (2) sections of ISPE GPP worth noting are those to do with the protocol format (Section II) and archiving (Section VII)…why?:
      • Guidance on Protocol Format – Other than the EMA PASS protocol template, there is no national guidance on the protocol format for non-interventional studies (as per Section II of ISPE GPP; ref 5).
      • Guidance on Document Archiving – “Where there are no specified national or regional requirements for retention of study materials, the archive should be maintained for at least five years after final report or first publication of study results, whichever comes later” (as per Section VII of ISPE GPP; ref 5).
    • ISPE GPP does cover ‘reporting of adverse drug events’ (Section 6), but this should be read, with due care and caution, as national pharmacovigilance requirements should always be complied with;
    • A limitation of ISPE GPP as best practice guidance for observational studies is that the document is not very detailed compared to the clinical trial equivalent (ICH GCP; ref 1).

ISPE GPP – Regulators Recommend ‘Consideration’ of these Guidelines

The International Society of Pharmacoepidemiology – Guidelines for good pharmacoepidemiology practices (ISPE GPP; ref 5) are a set of scientific guidelines that regulators recommend we should CONSIDER when conducting observational studies – note the emphasis on ‘consideration’ rather than imposing a legal mandate, which would be a ‘must comply with’ requirement:

    • CANADA – …fifteen key elements that should be considered for each protocol, and are reflective of…“The Guidelines for Good Pharmacoepidemiology Practices (GPP)” (Health Canada – March 2019; ref 7)
    • EUROPEAN UNION – 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…These scientific guidelines include – Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP) (as per Section B.1. of GVP Module VIII; ref 8)
    • GERMANY – The observation plan is to be drawn up according to recognized recommendations of scientific or regulatory guidelines…for example “Guidelines for Good Pharmacoepidemiology Practices” (GPP) of the “International Society for Pharmacoepidemiology (ISPE) (as per the BfArM/PEI Recommendations – December 2019; ref 9) 
    • USA – The FDA 2005 guidance, the ISPE guidelines, the STROBE reporting framework, and the ENCePP methods checklist and guide provide general guidance applicable to all pharmacoepidemiologic safety studies (as per Section II.B of the FDA Guidance – Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets (May 2013)) [ref 10].

The Common ethical foundation for all Observational Studies is the Declaration of Helsinki [ref 6]. It provides the basic framework of requirements embodied in national regulations, namely:

    • Participation of patients must be voluntary.
    • Benefits of the research should outweigh the risks and burdens to the research participants.
    • The study design must be clearly described and justified in a research protocol.
    • The research protocol must be submitted for consideration, comment, guidance, and approval to the concerned REC before the study begins.
    • Each potential research participant must be adequately informed … and participant consent must be given freely.
    • Every precaution must be taken to protect the privacy of research participants and the confidentiality of their personal information.
    • Every research study involving human participants must be registered in a publicly accessible database before recruitment of the first subject.
    • Researchers, authors, sponsors, editors, and publishers all have ethical obligations with regard to the publication and dissemination of the results of research.
    • Reports of research not in accordance with the principles of the declaration should not be accepted for publication.

To summarise, at a global level:

    • ICH GCP is not applicable to observational studies
    • ISPE GPP is is a scientific guideline that regulators recommend sponsors of observational studies consider when designing and conducting observational studies

References

1. ICH GCP – Integrated Addendum to ICH E6(R1) for Good Clinical Practice E6(R2) (November 2016)

Link: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf

2. Framework for FDA’s Real-World Evidence Program (December 2018)

Link: https://www.fda.gov/media/120060/download 

3. Draft FDA Guidance Data Standards for Drug and Biological Product Submissions Containing Real-World Data (October 2021)

Link: https://www.fda.gov/media/153341/download 

4.  Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (December 2021)

Link: https://www.fda.gov/media/154714/download 

5. The International Society of Pharmacoepidemiology – Guidelines for good pharmacoepidemiology practices (ISPE GPP) (June 2015)

Link: https://www.pharmacoepi.org/resources/policies/guidelines-08027/ 

6. WMA Declaration of Helsinki – Ethical Principles for Medical research Involving Human Subjects (October 2013)

Link: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ 

7. Health Canada – Elements of Real World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle (March 2019)

Link: https://www.canada.ca/en/services/health/publications/drugs-health-products/real-world-data-evidence-drug-lifecycle-report.html 

8. EMA – Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 3) (October 2017)

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 

9. Joint recommendations of the BfArM and the PEI on application observations according to § 67 Para. 6 AMG and on the notification of non-interventional safety tests according to § 63f AMG of December 20th, 2019

Link: https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Zulassung/klin-pr/nichtInterventPruef/Gemeinsame%20Empfehlungen%20zu%20AWB%20und%20PASS.pdf?__blob=publicationFile&v=1 

10.  FDA Guidance – Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets (May 2013)

Link: https://www.fda.gov/media/79922/download 

RWR Insights – What GxPs are Applicable to Non-Interventional (Observational) Studies?2022-08-07T16:29:49+00:00
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