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Real World Evidence (RWE) 101 – Study Close-out

RWE 101 – Study Close-Out

Closing out an observational study involves several key steps to ensure that all study activities are concluded properly, and data integrity is maintained. Here are the typical activities involved:
 
[1] Data Lock and Validation: The first step in the study closeout process is to ensure all data is collected, cleaned, and ready for analysis. This involves resolving any outstanding queries, performing a final quality control check on the data, and then locking it for final analysis. This step also requires validation of data by checking the accuracy and consistency of the data collected.
 
[2] Disposition of Study Materials: Any remaining study materials, such as unused data collection forms or materials used for measurements, need to be disposed of appropriately. Any biological samples collected during the study also need to be handled as per the protocol and regulatory guidelines, which could mean returning, destroying, or continuing to store them, as agreed.
 
[3] Final Report Preparation: After data is locked and validated, the study team will analyse the data and prepare a final study report. This report content and format should follow regulatory requirements where applicable e.g., EU PASS Report.
 
[4] Archiving Study Documents: All study documents, including the study protocol, data collection forms, consent forms, and correspondence, should be properly archived according to the regulatory requirements and the company’s SOPs.
 
[5] Site Closeout Visits: If the study was performed across multiple sites, each site may need a closeout visit. These visits serve to confirm that all necessary activities have been completed, including data collection, storage or destruction of study materials, and archiving of site documents.
 
[6] Contract Closure: Finally, any contracts related to the study, such as those with study sites or service providers, need to be formally closed. This could involve confirming that all deliverables have been met, all payments have been made, and all obligations are fulfilled.
 
[7] Notification of End of Study: It’s important to inform the relevant ethical review board (IRB/REC) or regulatory authority that the study has ended, and provide them with a summary of the study’s findings, if required.
 
[8] Communicating Results: Depending on the nature of the study and its sponsorship, the results may need to be communicated to a variety of stakeholders. This could include the sponsor, study participants, health authorities, and potentially the wider scientific community through publications.
 
These activities help ensure that the study is closed out in a systematic and organized manner, which is critical for compliance, data integrity, and future use or inspection of the study data and materials. The exact nature and sequence of the activities may vary depending on the specifics of the study, the regulatory framework, and the procedures established by the sponsor.

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Real World Evidence (RWE) 101 – Study Close-out2023-08-07T18:36:39+00:00

Real World Evidence (RWE) – TMF Reference Model versus the Real-World Study Document Index (RWS-DI)

RWE 101 – TMF Reference Model versus the Real-World Study Document Index (RWS-DI)

The Real World Study-Document Index (RWS-DI) is a framework developed by a working group of RWE experts to address the challenges of filing essential documents for non-interventional and observational studies. The RWS-DI is designed to be consistent with the TMF Reference Model (TMF RM) format and structure, but removes artifacts specific to clinical trials and replaces terminology to reflect the unique nature of real-world studies.
 
Key differences between the TMF Reference Model (TMF RM) and the Real World Study-Document Index (RWS-DI) are:
 
[1] TMF Reference Model:
– An industry-adopted reference structure for the TMF that takes the form of an index.
– Provides a model of a complete TMF, which can then be customized as needed for a specific clinical study.
– Assigns documents to a comprehensive taxonomy complete with standard nomenclature to enable consistent filing.
– Developed primarily from a sponsor perspective, which makes it difficult for sites to adopt due to its larger scope and non-intuitive terminology.

Link: https://lnkd.in/eV4cH4At
 
[2] Real World Study-Document Index:
– A framework developed by a working group of real-world study (RWS) experts to address the challenges of filing essential documents for non-interventional and observational studies.
– Based on a prospective study design to provide maximum coverage of the potential document or artifact types across the range of real-world study designs.
– Designed to be consistent with the TMF RM format and structure, but removes artifacts specific to clinical trials and replaces terminology such as “trial” with “study” and “subject” with “patient.”
– A stand-alone deliverable that is expected to evolve to reflect user community requirements.

Link1: https://lnkd.in/eNUnsKR6
Link2: https://lnkd.in/eU6vf8qN
 
Overall, it is important for organizations to understand the regulatory requirements for TMF management and determine which framework is best suited for their specific study design.

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Real World Evidence (RWE) – TMF Reference Model versus the Real-World Study Document Index (RWS-DI)2023-08-07T18:29:01+00:00

Real World Evidence (RWE) 101 – ISF vs TMF

RWE 101 – ISF vs TMF

Investigator Site File (ISF) and Trial (Study) Master File (TMF) are key elements in managing clinical and observational studies. They are distinct but interconnected, and play vital roles in ensuring the documentation, compliance, and overall management of a research study is handled properly.

[1] Investigator Site File (ISF): This is a collection of documents, images, and digital media that an investigator (or a site conducting the research) uses to record the administrative and procedural documentation related to the study. It includes items such as the protocol, study approvals, consent forms, participant information, communication records, and site-specific documentation. The ISF helps demonstrate the site’s compliance with the principles of Good Clinical Practice (GCP) and the applicable regulatory requirements.

[1] Trial Master File (TMF): This is a collection of essential documents that allow the conduct of a clinical trial to be reconstructed and evaluated. It is intended to serve both the interests of the sponsor and the regulatory bodies. The TMF includes a broad range of information, such as the protocol, ethics committee approval, data safety monitoring board reports, informed consent forms, and any other relevant documentation. It should include all the key documents from the ISF, but also additional information at a study-wide level.

Key differences between the ISF and TMF include:

[1] Scope: ISF focuses on documentation at the site level, specific to each location where the study is conducted. TMF encompasses the entire study and includes all sites involved in the study, maintaining a complete record of all essential documents.

[2] Control: ISF is usually maintained by the investigator or staff at the site where the study is being conducted. The TMF, on the other hand, is typically managed and controlled by the study sponsor.

[3] Documentation: While both files hold critical study documents, the ISF is more focused on site-specific operational documents (e.g., informed consent forms), while the TMF has more strategic and overall study control documents.

[4] Purpose: While both files are crucial for audits and inspections, the ISF is particularly important for demonstrating the compliance of the individual site, while the TMF helps provide a comprehensive overview of the study’s conduct and ensures that the trial can be adequately reconstructed if necessary.

Please note that while these are general guidelines, the exact nature of the ISF and TMF may vary depending on the specifics of the study, the regulatory framework, and the procedures established by the sponsor.

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Real World Evidence (RWE) 101 – ISF vs TMF2023-08-07T18:20:46+00:00

Real World Evidence (RWE) 101 – Study Conduct

RWE 101 – Study Conduct

Once the study has been set up, the study conduct phase begins. This phase includes several key activities that ensure the smooth running of the study and the collection of high-quality data. Here are some of the key study conduct activities in the context of Real-World Evidence (RWE) studies:
 
[1] Patient Enrolment and Follow-up: After obtaining informed consent, patients are enrolled in the study according to the criteria outlined in the study protocol. The enrolled patients and/or their healthcare data are then followed up at regular intervals. Observational study designs seek to mirror routine clinical practice as closely as possible.
 
[2] Data Collection: This involves gathering data according to the study protocol. The data can come from a variety of sources, such as electronic health records (EHRs), insurance claims databases, patient registries, or directly from patients via surveys or interviews. Data collection must be systematic and standardized to ensure data quality and reliability.
 
[3] Monitoring and Quality Control: Monitoring is done (recommended by the FDA and AEMPs) to ensure that the study is being conducted according to the protocol and that data is being collected accurately and consistently (especially safety data). This could involve site visits by clinical research associates, remote monitoring, or data audits.
 
[4] Safety Monitoring: Any adverse events or side effects reported by patients to/by clinicians are recorded and reported to the appropriate authorities. Reporting requirements differ by region.
 
[5] Interim Analysis: Depending on the study design, interim analyses may be conducted at certain points during the study. This can allow early detection of safety issues or indications of effectiveness.
 
[6] Vendor Management: If vendors are being used for services such as data analysis or lab testing, regular communication is required to ensure that the work is being done according to the agreed timelines and standards.
 
[7] Regulatory Compliance: Throughout the study, all(regional) regulatory requirements must be followed. This includes maintaining proper documentation, protecting patient privacy, and reporting to regulatory bodies as required.
 
[8] Communication and Reporting: Regular updates about the study progress are typically provided by the study sponsor, to the investigators, the ethics committee or IRB, and any other relevant stakeholders.
 
These activities continue until all patients have been enrolled and all data has been collected. The study conduct phase is critical for ensuring that the data collected is reliable and that the results of the study will be scientifically valid and useful for informing healthcare decisions.

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Real World Evidence (RWE) 101 – Study Conduct2023-08-07T18:13:03+00:00

Real World Evidence (RWE) 101 – Monitoring

RWE 101 – Monitoring

Monitoring requirements for Real-World Evidence (RWE) studies may differ from those of traditional randomized controlled trials due to the nature of data collection and the sources of data involved.
 
According to recent (2021) draft FDA Guidance: Study monitoring may be focused on maintaining the reliability of the RWD and data integrity, beginning with extraction of the data from its origin through data curation and transformation and reporting of results.
 
Here are the key monitoring considerations for RWE studies:
 
[1] Data Quality and Integrity: This is the core of any monitoring activity. In RWE studies, data is often sourced from electronic health records, claims databases, registries, or directly from patients. The accuracy and consistency of this data should be monitored to ensure its validity. This can involve cross-checking data from different sources, checking for missing or inconsistent data, and using statistical methods to identify potential data errors.
 
[2] Regulatory Compliance: Even though RWE studies often use pre-existing data, they still need to comply with relevant regulations. For example, patient data must be handled in accordance with data protection laws such as the General Data Protection Regulation (GDPR) in the EU or the Health Insurance Portability and Accountability Act (HIPAA) in the US.
 
[3] Protocol Adherence: While protocol deviations may be less of a concern with RWE studies than with traditional trials (since there is no intervention being delivered), it’s still essential to monitor whether the study is being conducted as planned. For example, are the correct data elements being collected, and is the data being analysed according to the pre-specified plan?
 
[4] Safety Monitoring: Even though RWE studies are typically observational and don’t involve interventions, they still need to monitor for any potential safety signals that emerge. For instance, if the study involves a drug or device, any adverse events or side effects reported in the data nust be investigated.
 
[5] Ethical Compliance: Even though the patients involved in RWE studies may not be directly participating in the way they would in a clinical trial, ethical considerations still apply. If the study involves direct contact with patients (e.g., via surveys), the consent process and protection of patient rights should be monitored.
 
[6] Analysis and Reporting: As data is collected and analysed, it should be checked for completeness and accuracy. Any interim analyses or final reports should be reviewed to ensure they accurately represent the data collected and follow the pre-specified analysis plan.
 
In summary, while the specifics of monitoring may vary somewhat, the goal remains the same: to ensure the study is conducted with high standards of quality, integrity, and ethics, and that the data collected is reliable and valid.

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Real World Evidence (RWE) 101 – Monitoring2023-08-07T17:56:59+00:00

Real World Evidence (RWE) 101 – eConsent

RWE 101 – eConsent

Electronic consent or eConsent refers to the process of using electronic systems and processes to convey information related to the study and to obtain and document participant consent. While eConsent brings numerous benefits to the table, such as improved participant comprehension, streamlined workflows, and easier tracking and managing of consent versions, it is not universally accepted in Real-World Evidence (RWE) studies due to several reasons:

[1] Regulatory Variations: Regulatory guidelines and requirements vary across different jurisdictions and countries. Some regions may not yet have clear guidance or regulations that specifically endorse eConsent, causing uncertainty about its legal validity.

[2] Digital Divide: While digital technologies are pervasive (increasingly accepted), access to and familiarity with these technologies is not universal. Some potential study participants may lack the technology needed for eConsent or may not be comfortable using it, which could potentially exclude certain populations from participation (introducing bias).

[3] Data Security and Privacy Concerns: As with any digital system, there are concerns related to data security and privacy. Participants may worry about their personal information being mishandled or leaked, especially given the sensitivity of health data.

[4] Implementation Costs: Setting up a secure, user-friendly eConsent system that can also meet all regulatory requirements is a significant investment. Small research entities or those in low-resource settings might find it challenging to bear these costs.

[5] Technical Hurdles: eConsent systems require a level of technical infrastructure and support to function effectively. This can include the need for reliable internet connectivity, ongoing technical support, regular software updates, and more.

Despite these challenges, the adoption of eConsent is increasing due to the evolution of technology, better regulatory support, and the COVID-19 pandemic necessitating remote study processes. As these challenges are addressed over time, it’s expected that eConsent will become a more universally accepted practice in RWE studies.

 

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Real World Evidence (RWE) 101 – eConsent2023-08-07T17:48:32+00:00

Real World Evidence (RWE) 101 – Consent to Participate in Research vs Consent to Access and Process Sensitive Healthcare Data (GDPR)

RWE 101 – Consent to Participate in Research vs Consent to Access and Process Sensitive Healthcare Data (GDPR)

Consent to participate in research and consent to access and process sensitive healthcare data are two different but overlapping types of consent, each governed by distinct legal and ethical principles. In the context of Real-World Evidence (RWE) studies:

[1] Consent to Participate in Research: This is the informed consent given by individuals to participate in a research study. Informed consent is a process by which researchers provide potential and enrolled participants with information about the study (purpose, procedures, risks, benefits, alternatives), and the participants voluntarily agree to participate. This consent can be withdrawn at any time, at which point the individual’s participation in the study would end.

[2] Consent to Access and Process Sensitive Healthcare Data: This relates to the consent given by individuals to have their personal and sensitive health data accessed and used for specific purposes, such as research. This type of consent is governed in Europe by the General Data Protection Regulation (GDPR). Under the GDPR, the use of health data is considered a processing of special category data and requires explicit consent, which must be freely given, specific, informed, and unambiguous.

In a RWE study, both types of consent may be (are) needed. The first ensures that participants agree to be part of the study and understand what will happen during the study. The second ensures that participants agree to their data being used in the manner specified, and it provides protections around how their data can be stored, transferred, and otherwise processed.

One key difference between these two types of consent is that withdrawal of consent to participate in the research study generally means the individual will not be part of the study going forward, but it does not necessarily mean that the data collected up to that point cannot be used. In contrast, under the GDPR, if an individual withdraws their consent to data processing, not only does the data processing have to stop, but in many cases, the data collected up to that point cannot be used further and may need to be deleted.

Another difference is that, while there are legal and ethical requirements to obtain informed consent for research participation in most cases, there are certain circumstances under which health data can be processed for research purposes under the GDPR without obtaining explicit consent, such as if the processing is necessary for reasons of public interest in the area of public health, or if the data has been anonymized.

In both cases, the principles of transparency, respect for persons, and their autonomy are paramount. Proper management of both types of consent is crucial for ethical research and for maintaining trust with study participants.

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Real World Evidence (RWE) 101 – Consent to Participate in Research vs Consent to Access and Process Sensitive Healthcare Data (GDPR)2023-08-07T17:41:42+00:00

Real World Evidence (RWE) 101 – Patient Retention

RWE 101 – Patient Retention

 

Long-term Real-World Evidence (RWE) studies face significant challenges when it comes to patient retention, for several reasons:

[1] Time Commitment: Participants in RWE studies are often required to participate over extended periods, sometimes even years. This long-term commitment may lead to decreased interest and attrition over time, especially if the participants do not see immediate benefits from their participation.

[2] Life Changes: Given the long-term nature of RWE studies, life events such as changes in health status, relocation, changes in personal or financial circumstances, or simply a change in priorities can influence a participant’s ability or desire to continue in the study.

[3] Perceived Burden: Depending on the design of the study, the level of participant engagement required can vary widely. Some RWE studies may require frequent hospital visits, self-reporting of data, regular lab tests, or other potentially time-consuming activities. The perceived burden of these requirements can negatively impact retention.

[4] Lack of Engagement: If participants feel that they are just data points and do not feel personally engaged or valued, they may be more likely to drop out of the study. Personal engagement strategies, regular communication, and feedback are therefore crucial to keep participants motivated.

[5] Privacy and Data Security Concerns: In the era of digital health data, participants might worry about the potential misuse of their personal health information, which may lead to dropouts.

[6] Inadequate Understanding: If the participants do not fully understand the importance of their role, the relevance of the research, or the potential benefits to them or to society, they may be less likely to continue in the study. Education and clear communication are key to ensuring participants understand these aspects.

To address these challenges, researchers are increasingly looking to use technologies and strategies that can improve the participant experience and maintain engagement over time, such as remote monitoring technologies, digital health platforms, personalized engagement strategies, and clear, ongoing communication about the value and impact of the study.

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Real World Evidence (RWE) 101 – Patient Retention2023-08-07T17:33:26+00:00

Real World Evidence (RWE) 101 – Patient Recruitment

RWE 101 – Patient Recruitment

Real-world evidence (RWE) is health care information derived from real-world data (RWD). It can be generated through various study designs or analyses, including pragmatic clinical trials, observational studies, and health surveys. In the context of RWE, patient recruitment plays a significant role, as the data collected from these individuals helps in understanding the effectiveness, safety, and usage of medical products in the real world.

Traditional Patient Recruitment: In traditional methods, patient recruitment generally happens through methods like physician referrals, media advertising, patient registries, and patient advocacy groups. This method can be time-consuming, costly, and sometimes inefficient, as it often relies on manual efforts. It can also be challenging to find patients who fit specific inclusion and exclusion criteria for a particular study.

AI-Enabled Recruitment: Artificial intelligence (AI) has started transforming patient recruitment in many ways. AI can analyze vast amounts of real-world data from electronic health records (EHRs), medical claims, health surveys, and other digital health platforms to identify eligible patients rapidly. This approach reduces the recruitment timeline and the costs associated with patient enrollment.

AI algorithms can predict the likelihood of patients participating in the study, improving the precision of recruitment. They can also monitor and analyze patient behavior, enabling the refinement of recruitment strategies in real-time. AI can further enhance the diversity of recruited patients by considering a wide range of demographic and geographic factors, leading to a more inclusive and representative study.

AI-enabled recruitment can also help in mitigating potential biases in patient selection by utilizing a data-driven approach. By analyzing historical clinical trial data, AI models can identify patterns and biases in previous studies and correct them in future ones. Furthermore, AI can help in patient retention by predicting the potential drop-out risks and enabling timely intervention.

In conclusion, while traditional methods are essential and remain relevant in certain contexts, AI-enabled recruitment offers the possibility of increased speed, reduced costs, and improved diversity and representativeness of patients in studies generating real-world evidence.

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Real World Evidence (RWE) 101 – Patient Recruitment2023-08-07T17:26:18+00:00

Real World Evidence (RWE) 101 – HARPER

RWE 101 – HARPER

Regulatory agencies, health technology assessors, and payers are increasingly interested in studies that make use of real-world data to inform regulatory and other policy or clinical decision-making. However, concerns over the credibility of real-world evidence studies have led to calls for more transparency on the design and conduct of RWE studies.
 
A joint task force between ISPE and ISPOR created a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The HARPER template provides clarity, structure, and a common denominator regarding the level of operational detail, context, and rationale necessary in a protocol.
 
HARPER = HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects
 
Link: https://lnkd.in/erkyU2iT
 
Four protocol templates were identified for RWE studies:
 
1. The European Medicines Agency’s (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Module VIII – post-authorizations safety studies (PASS) template,
2. ISPE’s guidelines for good pharmacoepidemiology practice (ISPE GPP) section on protocol development,
3. The National Evaluation System for health Technology (NEST) protocol guidance, and
4. The Structured Template and Reporting Tool for Real World Evidence (STaRT-RWE).
 
The HARPER protocol contains nine sections, including a title page, abstract, and a table for amendments and updates. Each section includes structured free text, a structured table, or a figure, and a free-text section to lay out context and rationale for scientific choices.
 
The study design diagram shows the context and rationale for the study setting, time 0 (index date), inclusion criteria, exclusion criteria, variables, exposure, outcome, follow up, covariates, sensitivity analyses, data sources, metadata, and software used in the study.
 
The data sources section includes a free text component followed by a structured table for specifying data sources. The data sources section can also include a detailed evaluation of the fitness-for-purpose of data source options.
 
Overall, the HARPER framework is a valuable resource for researchers and clinicians who are planning or conducting RWE studies. The framework can help to ensure that protocols are well-designed and will produce high-quality evidence.

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Real World Evidence (RWE) 101 – HARPER2023-08-07T17:19:12+00:00
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