“Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research”

[as per §36 of the Declaration of Helsinki: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/]

As researchers, we have an ethical obligation to publish our results, both positive and negative.  This ensures that participants are not exposed to unnecessary duplicate experiments that  may have no benefit for either the participant or science or society.

Why do we need ethics committee approval to be able to publish our non-interventional study results?  It’s an ethical obligation [see §23 of the Declaration of Helsinki] and a legal requirement.

The International Committee of Medical Journal Editors (ICJME) has embraced the principles of the Declaration of Helsinki in their recommendations to those wishing to publish their clinical research results.

Specifically, the ICJME require:

1. Evidence of Ethics Committee Approval: All investigators should ensure that the planning, conduct, and reporting of human research are in accordance with the Helsinki Declaration as revised in 2013. All authors should seek approval to conduct research from an independent local, regional or national review body (e.g., ethics committee, institutional review board), and be prepared to provide documentation when requested by editors.
2. Evidence of Informed Consent: Patients have a right to privacy that should not be violated without informed consent. When informed consent has been obtained, it should be indicated in the published article.

[ICJME Recommendations – Protection of Research Participants: https://www.icmje.org/recommendations/browse/roles-and-responsibilities/protection-of-research-participants.html]

In essence, to publish results from non-interventional studies, researchers must comply with ICMJE guidelines, which require adherence to the Declaration of Helsinki and relevant local regulations. This includes securing ethics committee approval, safeguarding participant privacy, and obtaining informed consent for publication. These steps underscore the importance of ethical integrity and transparency in research.

Data retention and archiving in non-interventional studies (NIS) are foundational practices that support the integrity of the scientific process, comply with regulatory requirements, facilitate future research, serve educational purposes, and ensure ethical management of study data. These practices are essential for advancing knowledge, fostering innovation, and ultimately improving health outcomes.

In many jurisdictions, regulatory bodies mandate the retention of research data for a specified period (see below).

Argentina = 2 years
Austria = 15 years
Brazil = 5 years
Germany = 10 years
Japan = 5 years
Netherlands = 15 years
South Korea = 3 years
Turkey = 5 years

Pain Point #1 = Most countries don’t define how long you should retain NIS  documents. In these cases, we recommend you defer (refer) to IPSE GPP data retention guidance = At least 5 years after final report or first publication of study results.

Pain Point #2 = Trying to force your non-interventional (observational)  study documents into a filing system designed specifically for clinical trials. There is a (reasonably) simple solution for this.  Use the real world study document index that was developed from the TMF Reference Model by NIS experts who were keen to mitigate this pain.

CDISC Real World Study Document Index: https://www.cdisc.org/sites/default/files/2023-09/Real_World_Studies_Document_Index_v1_2020_07_29.xlsx

CDISC TMF Reference Model: https://www.cdisc.org/tmf

In conclusion, through adherence to established guidelines and the utilization of resources like the CDISC Real World Study Document Index, researchers can navigate the complexities of data retention, thereby contributing to the broader goals of enhancing knowledge, spurring innovation, and improving global health outcomes.

Closing a non-interventional (observational) study involves several key activities to ensure the study is concluded ethically (and respectfully), the data is handled appropriately, and findings are disseminated (shared) effectively. These activities can be grouped into several categories:

1. Data Management and Analysis: Ensure all data collection is complete, including any follow-up information. Check the data for accuracy, completeness, and consistency. Perform the final analyses as per the statistical analysis plan. Once the data analysis is complete and verified, the database should be locked to prevent any further changes.
2. Ethical and Regulatory Compliance: Inform the ethics committee(s) (and competent authorities where applicable) about the study’s completion according to national reporting requirements and timelines.
3. Documentation and Reporting: Prepare a report that includes the study objectives, methodology, results, safety data and conclusions. Plan for the publication of study findings through scientific articles, conference presentations, and reports to stakeholders (participants, patient advocacy groups, etc.). Notify the relevant public databases (e.g., clinicaltrials.gov) that they study has closed and provide a summary of the results and/or links to publications.
4. Study Close-out Visit (if applicable): For studies with physical sites, if needed, conduct close-out visits to ensure all study-related materials are accounted for (e.g., unused data collection tools) and to debrief site staff. One of the (many) benefits of observational studies is there is no drug…and therefore no need for drug reconciliation.
5. Participant Communication: Notify participants (patients) about the study’s completion, thank them for their involvement and share the results with them.
6. Financial and Contractual Closure: Ensure all financial matters related to the study, such as payments to vendors or sites, are settled. Review and close any contracts related to the study, ensuring all obligations have been met.

Each of these activities requires careful planning and execution to ensure the study is closed responsibly and efficiently. The specifics may vary based on the study’s design, the national regulatory requirements.

The drug safety data generated by clinical trials demonstrates that the benefit-risk profile of the new drug (or approved drug with a proposed new purpose) is favourable for the condition being treated and is pivotal to support the application to market the drug. Whereas, the real world evidence (RWE) generated by non-interventional studies is used to confirm that the benefit-risk profile of the now approved drug continues to be favourable to the patient  when used in real life settings.

The safety reporting requirements for non-interventional studies are different to those for clinical trials as illustrated below in the context of Europe:

CLINICAL TRIAL SAFETY REPORTING

[as per Articles 42, 43 and Annex III of Regulation EU/536/2014]

1. Suspected Unexpected Serious Adverse Reactions (SUSARs) = 7 days (fatal or life threatening)
2. Suspected Unexpected Serious Adverse Reactions (SUSARs) = 15 days (other)
3. Serious Adverse Reactions (SARs) = Annual report
4. Adverse Reactions/ Adverse Events = Annual Report

NON-INTERVENTIONAL STUDY SAFETY REPORTING (PRIMARY DATA)

[as per Article 107.3 of Directive 2001/83/EC, § VI.C.1.2.1 of GVP Module VI, and § VIII.B.4.2. of GVP Module VIII]

1. Serious Suspected Adverse Reactions (SSARs) = 15 days
2. Non-Serious Suspected Adverse Reactions (SARs) = 90 days
3. Adverse Events = Interim Analysis and Final Study Report

NON-INTERVENTIONAL STUDY SAFETY REPORTING (SECONDARY DATA)

[as per § VI.C.1.2.1 of GVP Module VI, and § VIII.B.4.2. of GVP Module VIII]

1. Adverse Reactions/ Adverse Events = Interim Analysis and Final Study Report

Additionally, any new information that may affect the benefit-risk balance of the

medicinal product should be communicated immediately in writing as an emerging safety issue to competent authorities of the Member States in which the product is authorised and the EMA.

It’s worth noting (and being aware) that the terminology used is also different to those for clinical trials.  For example, in the context of clinical trials an SAR is a ‘serious adverse reaction’, whereas in the context of a non-interventional study, an SAR is a ‘suspected adverse reaction’, underlining the importance of context in understanding these terms.

In conclusion, understanding the differences in safety reporting requirements between clinical trials and non-interventional studies is crucial for accurate drug safety evaluation. Clinical trials focus on establishing the initial benefit-risk profile of a drug, requiring prompt reporting of adverse reactions, including Suspected Unexpected Serious Adverse Reactions (SUSARs) within 7 to 15 days and annual reports for other adverse events. In contrast, non-interventional studies, which examine approved drugs in real-world settings, have different timelines, such as 15 days for Serious Suspected Adverse Reactions (SSARs) and 90 days for non-serious reactions, with additional reporting in interim and final study reports. The terminology used in safety reporting also differs between clinical trials and non-interventional studies, underlining the importance of context in understanding these terms.

Clinical trial regulations and ICH GCP require that clinical trials be monitored at an intensity proportionate to the risks (and potential risks) posed to the research participants.

The purpose of the monitoring in the context of clinical trials?

1. Verify that the rights, safety and well-being of subjects are protected
2. Verify that the data generated in the clinical trial are accurate, complete, and verifiable from source documents (= reliable and robust).
3. Verify that the conduct of the trial is in compliance with the currently approved protocol/ amendment(s), with GCP, and with the applicable regulatory requirement(s).

[as per §5.18 of ICH GCP (R2), Article 48 of Regulation EU/536/2014, and 21 CFR §312.53]

What about the monitoring requirements for non-interventional (observational) studies?

Very few countries provide guidance on the expectations and standards for monitoring of non-interventional studies. However, according to the 2023 FDA Guidance, study monitoring is one of the principal quality control activities critical to ensuring that:

1. The study is conducted according to the protocol
2. Data submitted to FDA are reliable
3. Data are appropriately protected

For non-interventional studies, monitoring should begin at the data extraction from RWD sources and focus on the protection of human subjects, as applicable, and on maintaining data integrity (= the completeness, consistency, and accuracy of data).

As part of study monitoring of a non-interventional study, sponsors should, at a

minimum:

1. Ensure that the RWD required by the protocol are accurate and consistent with the

source records

2. Ensure that prespecified plans (e.g., SAP), protocol, and study procedures (e.g., for

curation and transformation and reporting of results) were followed

3. Ensure that deviations from the prespecified plans and protocol and study procedures are identified and documented, and when necessary, promptly evaluated and remediated according to the significance of the deviations that have been identified

[FDA Guidance – Considerations for the Use of RWD and RWE To Support Regulatory Decision-Making (Aug 2023): https://www.fda.gov/media/171667/download]

In conclusion, monitoring in non-interventional studies involves verifying that appropriate consent has been given, verifying the consistency of RWD with source records, ensuring adherence to predetermined plans and study protocols, and effectively managing deviations. This approach reflects an overarching commitment to the protection of research participants and the integrity of the data in research, irrespective of the study design.