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Real World Evidence (RWE) 101 – ICH GCP (R3) – Real World Evidence Context

RWE 101 – ICH GCP (R3) – Real World Evidence Context

Revision 2 of ICH GCP caused confusion to those of us who work with non-interventional studies. The glossary claimed that a ‘clinical trial’ was synonymous with a ‘clinical study’ (Section 1.12 of ICH GCP(R2)). This works if you conduct clinical trials (they are a type of clinical study), but not if you conduct non-interventional studies, which are a type of ‘clinical study other than a clinical trial’ (Article 2.2(4) of Regulation EU/536/2014).

The (draft) Revision 3 of ICH GCP, makes it clear “This guideline applies to interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities. This guideline may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorisation applications in accordance with local requirements.”

Also, the new definition of ‘clinical trial’ provided in the Glossary, removes any confusion regarding clinical trial vs clinical study.

Clinical Trial = Any interventional investigation in human participants intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

The emphasis in ICH GCP(R3) is on ‘interventional’ investigations, although the term ‘intervention’ is missing from the Glossary…as well as most national clinical trial regulations. This may cause trialists some difficulties in the coming years when asked ‘what makes my non-interventional study…interventional?’

This revision to the clinical trial definition and explicit emphasis on ‘interventional clinical trials’ is a positive (constructive) move in the context of real world evidence as it removes the previously unnecessary confusion caused by revision 2 (i.e., clinical trial = clinical study).

The concept paper for Annex 2 was published on 28 April 2023, with the draft expected in 12 – 18 months. Annex 2 is of relevance to RWE because it will include additional considerations on how GCP principles may be applied across a variety of trial designs and data sources, where applicable. This will include:

1. Decentralised elements, where some or all trial-related activities occur at locations other than traditional clinical trial sites, and data collection may occur remotely.

2. Pragmatic elements, reflecting trials that closely resemble routine clinical practice.

3. Real-world data (RWD) sources [not including observational studies], for example, the use of registries, electronic health records (EHR), hospital data, pharmacy and medical claims data or wearables

Next? Is it time for similar harmonised guidelines for ‘non-interventional studies’?

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Real World Evidence (RWE) 101 – ICH GCP (R3) – Real World Evidence Context2023-08-09T15:27:28+00:00

Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

RWE 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

No, “clinical study” and “clinical trial” are not necessarily synonymous in the context of non-interventional studies in the EU.

In general, a clinical study refers to any investigation involving human participants that is intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products, or to identify any adverse reactions to one or more medicinal products. This can include both (interventional) clinical trials and non-interventional studies.

A clinical trial, on the other hand, specifically refers to a type of interventional clinical study where one or more medicinal products are tested in human participants with the aim of evaluating their safety and/or efficacy i.e., there is a treatment intervention involving a medicinal product.

Non-interventional studies (NIS) are observational studies that do not involve any treatment interventions or protocol-dictated administration of a medicinal product. They are designed to observe patients in their natural clinical setting and collect data on the outcomes of a specific drug or treatment intervention.

So, while a clinical trial is a type of clinical study, not all clinical studies are clinical trials.
 
Revision 2 of ICH GCP caused confusion to those of us who work with non-interventional studies. The glossary claimed that a ‘clinical trial’ was synonymous with a ‘clinical study’ (Section 1.12 of ICH GCP(R2)). This works if you conduct clinical trials (they are a type of clinical study), but not if you conduct non-interventional studies, which are a type of ‘clinical study other than a clinical trial’ (Article 2.2(4) of Regulation EU/536/2014).
 
The (draft) Revision 3 of ICH GCP includes a new definition of ‘clinical trial’ provided in the Glossary, which removes any confusion regarding clinical trial vs clinical study.

Clinical Trial = Any interventional investigation in human participants intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

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Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?2023-08-07T12:48:43+00:00

Real World Evidence (RWE) 101 – Is ICH GCP Applicable to Non-Interventional Studies?

RWE 101 – Is ICH GCP Applicable to Non-Interventional Studies?

No, the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines are not applicable to non-interventional studies (NIS) in the context of real-world evidence (RWE).

ICH GCP guidelines are designed to ensure the protection of human subjects and the quality and integrity of data generated in clinical trials of investigational medicinal products (IMPs). In contrast, NIS are observational studies that do not involve the administration of IMPs, and instead rely on the collection of data from routine clinical practice or other non-experimental settings.

However, there are other guidelines and frameworks that apply to non-interventional studies in the context of real-world evidence, such as the International Society for Pharmacoepidemiology’s (ISPE) “Guidelines for Good Pharmacoepidemiology Practices” (GPP).

It is important to note that while NIS may not be subject to the same regulatory requirements as clinical trials, they still need to adhere to the applicable local regulations, ethical and scientific standards, and to ensure the protection of patient privacy and confidentiality.

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Real World Evidence (RWE) 101 – Is ICH GCP Applicable to Non-Interventional Studies?2023-08-07T22:57:28+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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