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):

• • Observational Study = A non-interventional clinical study design that is by definition, not considered a clinical trial (as per the Glossary of the Framework for FDA’s Real-World Evidence Program) [ref 2].
  • Non-Interventional (Observational) Study = A type of study in which patients are not assigned to a study arm according to a protocol, but instead receive the drug of interest during routine clinical care (as per the Glossary of the Draft FDA Guidance Data Standards for Drug and Biological Product Submissions Containing Real-World Data, October 2021) [ref 3].
  • Clinical trial legislation is not applicable to non-interventional studies: 
    • • According to the recent FDA guidance, non-interventional (observational) studies are not clinical investigations (clinical trials) as defined under § 312.3 and do not require an IND (as per Section III.A of the 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, 8 December 2021) [ref 4].

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