“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.

Informed consent in the context of RWE studies in Europe is subject to various regulations and ethical standards, which can differ based on the type of study and the data being used.

1. Explicit Informed Consent: This is the ‘traditional’ model of informed consent (as per Section 25 to 32 of the Declaration of Helsinki) where participants are given detailed information about the study, including its purpose, duration, required procedures, risks and benefits, and their rights as participants. After receiving this information, participants must explicitly agree to take part in the study.
2. Broad Consent: For studies that intend to use data (and/or biosamples) for a range of research purposes over an extended period, broad consent may be possible. This type of consent involves participants agreeing to the use of their data (and/or biosamples) for various future research projects, which may not be fully defined at the time of consent. Broad consent is subject to strict regulations and oversight to ensure ongoing participant rights and data protection and may not be possible in certain regions e.g., Ireland.
3. Opt-out Consent: In some European countries (e.g., MR-004 compliance procedures for RIPH-3 studies in France) and contexts, an opt-out approach may be used. Here, patients’ data is included unless they explicitly state their desire not to participate.
4. Waiver of Consent: Under certain circumstances, regulatory bodies may grant a waiver of consent for a study. This usually happens when the research involves minimal (no additional risks above routine clinical practice) risk to participants, involves the use of existing data or biological specimens, and it would be impractical to obtain consent from all participants. However, this waiver is strictly regulated and must adhere to specific ethical and legal standards (e.g., Section 251 waivers in the UK).
5. Secondary Use of Data: When using existing data collected for a different primary purpose (e.g., clinical records), informed consent may vary. If the data is fully anonymous, informed consent is not required. However, if data can be linked back to individuals (pseudonymised), researchers typically need to obtain either a new consent or have an ethical/legal basis for the secondary use of data without re-consent.

Consent to participate in research and consent to access and process sensitive healthcare data (e.g., in the context of GDPR compliance) are two different but overlapping types of consent,

Each country within Europe currently has additional specific regulations and practices, making it crucial for researchers to be aware of both EU-wide and national requirements.  This may change in the context of the European Health Data Space, but for now you do need to be aware of (and comply with) the national requirements.

Patient recruitment for clinical trials and non-interventional studies differs in several key aspects, largely due to the nature and objectives of each type of study. Here’s a breakdown of the main differences:

Clinical Trials

(i) Purpose: Clinical trials are conducted to test the efficacy and safety of drugs, or medical devices. These are typically experimental in nature and are carefully designed to answer specific research questions.

(ii) Recruitment Criteria: Participants must meet specific inclusion and exclusion criteria that are relevant to the study’s objectives. These criteria can be quite strict, as the goal is to ensure that any observed effects are due to the drug or device being tested and not external factors. The research participants are recruited based on the condition or conditions they have, rather than they drugs they are taking,

(iii) Interventions: Participants are typically assigned to specific intervention groups (e.g., a new drug vs. a placebo). The allocation can be random (randomized controlled trials) and often blinded to reduce bias.

Non-Interventional Studies

(i) Purpose: Non-interventional studies (observational studies) aim to observe outcomes in a natural setting without attempting to modify the behaviour or condition of the participants. These studies can help identify patterns, causes, and effects in real-world settings.

(ii) Recruitment Criteria: While there may still be inclusion and exclusion criteria, these are generally less stringent than those for clinical trials. The aim is often to obtain a sample that is as representative of the general population or a specific population as possible. Crucially, the patients need to be taking the drug of interest to be eligible for inclusion in the study.

(v) Interventions: There are no assigned interventions (drugs or devices) in non-interventional studies. Instead, researchers collect data on the impact (safety and effectiveness) of the drug of interest that they are already taking as they occur naturally (in real life).

Patient recruitment for clinical trials versus non-interventional studies presents distinct challenges and methodologies, primarily due to the differing goals and structures of these research approaches. Clinical trials, which are experimental, aim to evaluate the efficacy and safety of drugs or medical devices through well-defined protocols and strict participant criteria to isolate the effects of the intervention. These trials often involve randomization and blinding to mitigate bias. On the other hand, non-interventional (observational) studies seek to understand outcomes in a natural setting, focusing on the real-world effectiveness and safety of treatments without altering participant behaviour or conditions. Recruitment criteria for these studies are more lenient to capture a broader, more representative sample of the population or specific patient groups, with participants being observed based on their existing treatment. This fundamental difference in purpose and methodology underscores the varied approaches required for patient recruitment in clinical trial versus observational research settings.

“Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.” [§35 of the Declaration of Helsinki] [1]

The registration of non-interventional studies on publicly accessible databases is a practice that embodies the ethical principles of the Declaration of Helsinki. It enhances transparency, accountability, participant protection, and the contribution to scientific knowledge, all of which are essential for conducting ethical research involving human subjects (research participants).

Recently, the FDA noted that “To ensure transparency regarding their study design, sponsors should post their study protocols on a publicly available website, such as ClinicalTrials.gov or the web page for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) for post-authorization studies” [2].

Registration of Imposed post-authorisation safety studies on the ENCePP PAS Register is a legal requirement, whereas registration on non-imposed studies is not.

Transparency and Accountability

Transparency – The Declaration emphasizes the importance of transparency in all research involving human subjects. By registering non-interventional studies, researchers make the study’s design, methodology, and goals publicly available. This openness helps build trust with the public and the research community by ensuring that the studies can be scrutinized and understood by others.

Accountability – Registering studies holds researchers accountable for the integrity of their research. It allows for the comparison of reported research outcomes with what was initially planned. This practice helps to prevent selective publication and reporting biases, ensuring that all results, whether positive, negative, or inconclusive, are accessible and can contribute to the body of scientific knowledge.

As the regulatory landscape continues to evolve, with entities like the FDA advocating for increased transparency in study designs and protocols, it becomes ever more critical for researchers to embrace the registration of both clinical trials and non-interventional studies. Doing so not only fulfils a legal and ethical mandate but also paves the way for a more informed and inclusive scientific inquiry that benefits all stakeholders involved.

References:

1. Section 35 of the World Medical Association – Declaration of Helsinki (October 2013): https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
2. Section III.B.2 of the FDA Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (August 2023): https://www.fda.gov/media/171667/download

The regulatory green light in the context of non-interventional studies plays a crucial role in ensuring that these studies are conducted ethically, legally, and responsibly. Despite the absence of an investigational medicinal product, which might suggest a simpler regulatory path compared to interventional studies, non-interventional studies still require rigorous oversight. This oversight is critical for several reasons:

[1] Ethical Considerations

Non-interventional studies, like all research involving human participants, are subject to ethical principles outlined in the Declaration of Helsinki. These principles are designed to protect the rights, safety, and well-being of research participants. The regulatory green light process ensures that research ethics committees (or institutional review boards) have reviewed the study’s ethical aspects, including the information provided to participants and the consent process. This step is vital to ensure that participants are fully informed about the study’s nature, their rights, and the use of their data, allowing them to make an informed decision about their participation.

[2] Legal Compliance

The approval process also verifies compliance with local laws and regulations governing research with human subjects. By obtaining the necessary approvals, study sponsors and investigators ensure that their study is legally permissible, protecting both the participants and the research entities from legal repercussions. This compliance extends to contractual agreements with research sites, further formalizing the study’s legal and ethical framework.

[3] Participant Recruitment and Data Collection

The regulatory green light signifies that all prerequisites for starting the study have been met, allowing for the ethical recruitment of participants and collection of data. This step is critical to ensure that the study can proceed smoothly without ethical or legal issues that could compromise the research’s integrity or necessitate its cessation.

[4] Moral and Professional Responsibility

Study sponsors and project managers bear a moral and professional obligation to ensure that their research adheres to the highest ethical and legal standards. This responsibility includes securing all necessary approvals before initiating any study activities. Failure to do so not only undermines the study’s ethical foundation but also risks damaging public trust in research practices and potentially harming participants.

[5] Ensuring Data Integrity and Research Validity

Regulatory approvals contribute to the integrity and validity of the research. Studies conducted with proper ethical and legal oversight are more likely to be recognized and accepted by the scientific community, regulatory authorities, and the public. This acceptance is crucial for the impact of the study’s findings on policy, clinical practice, or further research.

In summary, the regulatory green light in non-interventional studies is not merely a bureaucratic step; it is a fundamental component of responsible research conduct. It ensures ethical integrity, legal compliance, participant protection, and the overall validity of the study’s findings, highlighting the importance of this process in the broader context of generating reliable real-world evidence (RWE).

Study start-up activities for non-interventional studies and clinical trials involve different focuses and regulatory requirements due to the distinct nature of each study type. Non-interventional studies (observational studies) and clinical trials (interventional studies) differ fundamentally in their objectives, methodologies, and the extent of regulatory oversight. Below are key differences in their start-up activities:

1. Design and Protocol Development

– Clinical Trials: Focuses on creating a detailed protocol that outlines the study’s objective, methodology, statistical considerations, and organization. This includes the selection of the intervention, control/comparator groups, randomisation, and specific endpoints to be measured. The protocol must meet rigorous regulatory standards for ethics and patient safety.

– Non-Interventional Studies: The design focuses on observing outcomes in real life settings without healthcare interventions. The protocol outlines objectives, study population, data sources, and methods of data collection and analysis but is generally less stringent than for clinical trials.

2. Regulatory and Ethical Approvals

– Clinical Trials: Require extensive (risk proportionate) regulatory and ethical approvals before starting, including the submission of a clinical trial application to regulatory authorities (e.g., US FDA and EU EMA) and approval from Reseearch Ethics Committees (RECs). Although extensive, the approval requirements have , to a certain extent, been harmonised globally, helping to reduce duplication of effort.

– Non-Interventional Studies: Typically involve less stringent regulatory requirements i.e., most countries do not require submission to a regulatory authority (e.g., EMA or FDA) unless the study is a post-marketing requirement.  However, the specific approval requirements differ in every country meaning that, although the individual submission requirement may be simple, the management of differing submission requirements in multiple countries can be time-consuming and complex.

3. Site Selection and Feasibility

– Clinical Trials: Site selection is critical, with a focus on sites’ ability to recruit suitable participants, their experience with similar studies, and their infrastructure to manage the investigational product safely. Feasibility assessments are comprehensive, evaluating patient population, investigator qualifications, and facility capabilities.

– Non-Interventional Studies: Site selection focuses more on the availability of the drug in the country and site of interest i.e., has the drug been approved and is it being prescribed?

Secondary to this is whether the site has the time, resources, qualification, and experience to conduct the study.

In conclusion, although both types of studies play a crucial role in medical research advancement, the initial processes and hurdles for clinical trials and non-interventional studies can vary greatly. Contrary to common assumptions, the varied start-up demands for non-interventional studies across different countries can lead to a higher workload during the initiation phase for non-interventional studies spanning multiple countries compared to clinical trials.