RWR Insights – What GxPs are Applicable to Non-Interventional (Observational) Studies?
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):
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- 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:
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- 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].
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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)
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- 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:
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- 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:
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- 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:
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- 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)
7. Health Canada – Elements of Real World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle (March 2019)
8. EMA – Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 3) (October 2017)
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
10. FDA Guidance – Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets (May 2013)
RWR Insights | Quality Standards for Registries – EUnetHTA REQUEST Tool
APRIL 2022 – This is the third (3rd) and last in the series exploring current quality standards for registries and registry-based studies. This month we focus on quality standard expectations when using real world data (RWD) from registries to support Health Technology Assessment. Specifically, we’ll look in detail at the ‘Registry Evaluation and Quality Standards Tool (REQueST)’ tool developed by the European Network for Health Technology Assessment (EUnetHTA) [1] [2].
The use of registries is becoming increasingly common in health technology assessment (HTA) and regulation. There is a growing interest in the role of observational data in complementing experimental data. This project aims to support best practice in the collection, use and re-use of real world data, and explore options to support sustainable multi-stakeholder collaboration (as per Paragraph 1 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019) [3].
EUnetHTA – REQUEST Tool
For HTA purposes, the Registry Evaluation and Quality Standards Tool (REQueST) is designed to be used in 3 steps (as per Paragraph 13 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
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- Step 1: Initial screening of a potential registry for suitability. Standards currently presented in the ‘Methodological Information’ section of the tool are intended to enable a user to assess whether a registry can provide data that fulfil their needs6.
- Step 2: All registries that are potentially suitable should then be assessed against ‘Essential Standards’ relating to registry quality.
- Step 3: Some registries will require assessment against additional criteria for specific purposes (e.g., international collaboration on data collection will require interoperability). This is assessed in the ‘Additional Requirements’ section of the tool.
The registry owner carries out a self-assessment by completing the ‘registry owner’ column in the ‘Essential Standards’ worksheet of REQueST. This information together with a summary of the registry methodological information and the minimum key documents (listed in paragraph 32) are presented on the registry’s web site. These may be reviewed at any point by organisations considering whether to use the data in evidence development for HTA and regulatory monitoring to check if the information meets their needs (as per Paragraph 23 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019).
Periodic Review of Registries
In general, assessment of the quality of a registry cannot be done as a one-off event; ongoing quality needs to be demonstrated and the tool output will require periodic review (as per Paragraph 30 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019).
Criteria for the frequency of registry review could include the (as per Paragraph 30 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
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- Maturity of the registry and technology (e.g., national joint registries dealing with established technologies and governance would require less frequent review).
- Production of peer-reviewed publications based on the registry (e.g., if at least one peer-reviewed publication per technology is produced in an acceptable time interval, the REQueST review could be less frequent).
- Purpose of the registry (e.g., if it is bespoke, that is, to meet specific regulatory or technology assessment objectives, quality should be assessed at the beginning and at the point of data use).
It should be noted that the ‘Methodological Information’ and ‘Additional Requirements’ sections of REQueST include questions that relate to specific uses of a registry. Users of REQueST may therefore need to run the tool more than once for an individual registry, and only the ‘Essential Standards’ would be transferrable between assessments (as per Paragraph 31 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019).
All phases require the registry owner to produce and make publicly available the following ‘minimum key documents’ (as per Paragraph 32 of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
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- Registry aims and methodology including minimum data set and data security policies.
- Declarations of relevant interests.
- Demonstration of continuous and comprehensive data collection (exact format and periodicity to be agreed but this is likely to include regular reporting on coverage, completeness and validation of data). Where a registry is federated between many countries, a report would be required from every participating registry.
- Safety statement detailing any alerts that have been raised (initiated by the registry owner and jointly publicised with the regulator/assessor).
Methodological Information – Screen for registries whose data and methodology match the requirements of the HTA/regulatory study or research question(s)
‘Methodological Information’ refers to the research methodology and which information is collected (research question, protocol and observational methods). This section provides an opportunity for the HTA agency to gather information about the data collected by the registry. Methodological information will be used to assess whether a registry is ready and able to answer a specific research question. There are 8 ‘Methodological Information’ items covering the following areas (as per Appendix A of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
• Type of registry
• Use for registry-based studies and previous publications
• Geographical and organisational setting
• Duration
• Size
• Inclusion and exclusion criteria
• Follow-up
• Confounders
Essential Standards – Assessment of registry governance to assure general data quality and protection
‘Essential Standards’ are the minimum requirements for every registry. They are essential elements of good practice and evidence quality that can be used in the evaluation of the registry. Unless all essential criteria are demonstrably fulfilled, the HTA agency should not use the registry for evidence evaluation. There are 12 ‘Essential Standards’ items covering the following areas (as per Appendix A of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
1. Registry aims and methodology
2. Governance
3. Informed consent
4. Data dictionary
5. Minimum data set
6. Standard definitions, terminology and specifications
7. Data collection
8. Quality assurance
9. Data cleaning
10. Missing data
11. Financing
12. Protection, security and safeguards
Additional Requirements – Specific requirements for the evidence questions
‘Additional Requirements’ are elements of good practice and evidence quality which are not always practical or feasible to achieve but are useful to consider in planning and evaluating registries. Evaluation of the ‘Additional Requirements’ depends on the requirements of an individual HTA agency and the specific context or registry use (e.g., an international collaboration on data collection will require registry interoperability). There are 3 ‘Additional Requirements’ items covering the following areas (as per Appendix A of the EUnetHTA JA3 Vision Paper on REQueST Tool, September 2019):
• Interoperability and readiness for data linkage
• Data sources
• Ethics
References
1. Registry Evaluation and Quality Standards Tool (REQueST)
Link: https://www.eunethta.eu/request-tool-and-its-vision-paper/
2. European Network for Health Technology Assessment (EUnetHTA)
Link: https://www.eunethta.eu/
3. EUnetHTA JA3 Vision Paper on REQueST Tool (September 2019)
