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.

The necessity for insurance in research studies, including non-interventional studies and clinical trials, hinges on the potential risks and liabilities involved. Here’s a breakdown of why insurance may or may not be required for these different types of studies:

[1] Non-Interventional Studies = Non-interventional studies (observational studies) do not involve assigning specific treatments or healthcare interventions to participants. Instead, researchers observe participants in their normal setting or review existing records to gather data. Generally, non-interventional studies pose no more risk to participants than routine clinical practice (normal life) because the researchers do not influence the care or treatment the participants receive. As a result, insurance is not usually required for non-interventional studies (exceptions include Belgium). However, always check what the local insurance requirements are for your study type.  Ignorance is never an excuse.

[2] Clinical Trials = In the context of medicinal products, clinical trials involve administering new drugs or off-label approved drugs to research participants. The risk of harm to the research participants is higher than would be encountered during normal (routine) clinical practice.  As noted in the Declaration of Helsinki (§22) and ICH GCP (§5.8), the trial sponsor should “should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s)”.  Because of this, most (all?) countries require clinical trials to have insurance coverage as part of their regulatory approvals. This is to ensure that participants are protected and compensated for any trial-related injuries.

The key difference in the need for insurance between non-interventional studies and clinical trials lies in the level of risk and the potential for direct harm to the research participants. Clinical trials, especially those that test new medicinal products, carry inherent risks due to the unknown effects (in humans) of the treatments being tested. These risks necessitate a higher level of protection for both participants and researchers. On the other hand, non-interventional studies, which typically involve less direct interaction with participants and no alteration of their standard care, present lower risks, thereby reducing (negating) the need for insurance.

However, the specific requirements for insurance can vary widely depending on the country, the nature of the study, the type of data collected, and the potential risks involved. Researchers should always consult relevant regulations, guidelines, and regulatory bodies to ensure compliance with local laws regarding insurance coverage for their studies.