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Real World Evidence (RWE) 101 – Audits

RWE 101 – Audits

A quality assurance auditor in the context of a real-world evidence (RWE) study has several responsibilities, key among them ensuring that all facets of the study align with applicable regulations, guidelines, and established protocols. In a study conducted in multiple countries, each with their unique regulatory requirements, the auditor would typically focus on the following aspects:
 
[1] Regulatory Compliance: The audit evaluates whether the study aligns with the different regulatory requirements of each involved country. This also includes adherence to international standards and guidelines, such as the Declaration of Helsinki and ISPE GPP, which are recognized globally.
 
[2] Study Protocol Adherence: The audit checks whether the study is being conducted according to the approved protocol, evaluating the study’s procedures and operations for alignment.
 
[3] Informed Consent: The process of obtaining informed consent from participants is critical in RWE studies. The audit reviews this process to verify that consent is obtained appropriately and aligns with the local regulations and cultural norms of each country.
 
[4] Data Collection, Management, and Analysis: The audit examines the processes of data collection, storage, and analysis to ensure accuracy, consistency, and compliance with data privacy regulations. This involves evaluating any electronic data capture systems, as well as the procedures for data validation and error correction.
 
[5] Safety Reporting: The audit reviews the systems for reporting safety and adverse events, ensuring that all events are recorded and reported properly according to regulatory requirements. The audit also checks for appropriate responses to any adverse events.
 
[6] Personnel Training and Qualifications: An audit reviews the training records to confirm that all personnel involved in the study have the necessary qualifications and have received suitable training.
 
[7] Subcontractors and Vendors: If the study employs any subcontractors or vendors (e.g., laboratories or data management companies), the audit reviews their practices and procedures to verify their adherence to required standards.
 
[8] Study Reports: Lastly, interim and final study reports are reviewed to ensure they accurately represent the study data and meet all required standards for scientific reporting and regulatory submission.
 
These areas comprise the primary focus of a quality assurance audit for a multi-country RWE study. The overarching goal is to ensure that the RWE study is conducted ethically and appropriately, with reliable and accurate resulting data.

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Real World Evidence (RWE) 101 – Audits2023-08-07T21:01:15+00:00

Real World Evidence (RWE) 101 – Compliance Maps

RWE 101 – Compliance Maps

In the context of multi-country Real-World Evidence (RWE) studies, “Regulatory Compliance Maps” are essentially a detailed representation of the diverse regulatory requirements specific to each participating country.
 
RWE studies involve the analysis of data derived from a number of different sources outside of typical clinical trials, such as electronic health records (EHRs), medical claims and billing data, patient registries, and patient-generated data. Different countries have varied regulations regarding the use and sharing of such data, including the handling of patient privacy, data security, and informed consent among others.
 
To navigate through this complex landscape, regulatory compliance maps are created for several purposes:
 
[1] Understanding the Regulation: These maps help in identifying the specific regulatory requirements in each country. They define how to handle, process, store, and share patient data.
 
[2] Comparison: They also provide a comparative view of the regulatory landscape across different countries. This comparison allows companies to understand the relative complexity of conducting RWE studies in different regions.
 
[3] Planning: Based on these compliance maps, companies can strategise and design their RWE studies to ensure they meet all regulatory requirements. This might involve altering the study design or selecting specific data collection tools in different regions.
 
[4] Risk Mitigation: By understanding the specific regulations in each region, companies can take proactive steps to minimize risks associated with non-compliance, which might lead to legal repercussions or reputational damage.
 
[5] Collaboration: These maps also facilitate better communication and cooperation with local authorities, including IRBs/RECs, as they demonstrate the company’s understanding and respect for local regulations.
 
Creating and maintaining regulatory compliance maps can be a complex task due to the evolving nature of regulations, the diversity of data sources, and the need for expertise in different jurisdictional laws. However, it is an essential part of conducting efficient and ethical multi-country RWE studies.

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Real World Evidence (RWE) 101 – Compliance Maps2023-08-07T20:50:45+00:00

Real World Evidence (RWE) 101 – SOPs and Regional Regulations

RWE 101 – SOPs and Regional Regulations

In the realm of quality assurance (QA), it’s vital that standard operating procedures (SOPs) are crafted in a way that accurately and specifically reflects the control measures, tasks, and processes that the organization can directly influence and manage. Here are several reasons why it is not advisable to include processes in SOPs that you have no control over, such as country-specific regulations for Real-World Evidence (RWE) studies:
 
[1] Inaccuracy and Inconsistency: Country-specific regulations can vary significantly and may change over time. The organization has no control over these changes and thus cannot guarantee that their SOPs will stay up-to-date with the current regulations in each country.
 
[2] Potential for Non-Compliance: If the SOP includes processes dictated by external regulations that subsequently change, the company might unknowingly be in non-compliance. This could lead to regulatory consequences, including fines or other penalties.
 
[3] Confusion: Inclusion of country-specific regulations in the SOPs can cause confusion among the staff who are required to follow these procedures. If an SOP describes a procedure that is not applicable or is different in their specific context, this could lead to errors, misunderstandings, or non-compliance.
 
[4] SOP Management Complexity: SOPs should be as concise, clear, and easy to manage as possible. By including country-specific regulations, the SOPs become more complex and harder to maintain, which increases the risk of errors and decreases efficiency.
 
Instead of including country-specific regulations in SOPs, a better approach would be to make SOPs generic enough to accommodate various situations, while ensuring compliance with overarching international or regional regulations. Furthermore, local teams should be trained and have access to resources that detail the country-specific regulations applicable to them. They could also have local operating procedures or instructions that explain how the SOP should be implemented in light of these regulations.
 
Finally, there should be a process in place to ensure that the organization is constantly up-to-date with any changes in country-specific regulations and can adjust its procedures accordingly. This might involve dedicated personnel or teams, use of regulatory consultancy services, or subscription to regulatory update feeds. These processes would lie outside the SOPs, but would be critical to maintaining regulatory compliance.

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Real World Evidence (RWE) 101 – SOPs and Regional Regulations2023-08-07T20:02:24+00:00

Real World Evidence (RWE) 101 – Standard Operating Procedures

RWE 101 – Standard Operating Procedures

Standard Operating Procedures (SOPs) are critical for the operation of any business, particularly in regulated industries like pharmaceuticals where precision, safety, and compliance with regulatory requirements are paramount. For a pharmaceutical company, SOPs for observational studies and clinical trials should be separated due to the distinct nature and objectives of each type of study. Here are the main reasons:
 
[1] Different objectives: Clinical trials are experiments designed to evaluate the safety and efficacy of a new drug or intervention. On the other hand, observational studies are non-interventional; they involve the collection of data without altering the patients’ usual treatment or environment, aiming to observe and analyse patterns, effects, or outcomes.
 
[2] Regulatory requirements: Clinical trials are highly regulated, with strict GxP requirements from bodies like the FDA or EMA. Observational studies, while still regulated, do not fall under the same stringent GxP requirements. Having separate SOPs ensures compliance with the correct set of regulations for each type of study.

[3] Study design and conduct: The design and conduct of clinical trials and observational studies are significantly different. For instance, clinical trials are generally randomized, controlled, and blinded studies. In contrast, observational studies may involve case-control studies, cohort studies, or cross-sectional studies. Different SOPs can specify the appropriate designs, methods and checks for data collection, storage, and analysis in each case.

[4] Patient consent and confidentiality: In clinical trials, patients provide informed consent for the specific interventional treatment they will receive. In observational studies, while consent is still required, it’s often related to access and use of their medical data rather than a specific treatment. Thus, separate SOPs can address these differing requirements.
 
[5] Risk Management: Risks and safety considerations also vary between clinical trials and observational studies. The risks of clinical trials often relate to the new drug or intervention being tested, while observational studies’ risks typically concern data protection and patient privacy.
 
[6] Reporting Results: Different types of studies may also have different reporting requirements, including timelines, formats, and recipients of the information (e.g., regulatory authorities, ethics committees, sponsors).
 
By having separate SOPs, companies ensure that all these aspects are appropriately addressed, leading to better quality, more ethical research, and improved compliance with regulatory requirements. It also helps in training and guiding staff effectively in their roles for different studies.

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Real World Evidence (RWE) 101 – Standard Operating Procedures2023-08-07T19:53:39+00:00

Real World Evidence (RWE) 101 – Publications

RWE 101 – Publications

The term RWE stands for Real-World Evidence, which is evidence derived from real-world data (RWD). RWD are data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.
 
Ethical approval is needed for the publication of RWE studies in international peer-reviewed journals for several key reasons:
 
[1] Participant Protection: Ethical approval ensures that the rights, safety, and well-being of the study participants are protected. It guarantees that the study has been designed to minimize harm and discomfort to the participants.
 
[2] Informed Consent: Ethical review boards (RECs/IRBs) ensure that participants have given informed consent. This means participants are made aware of the nature of the study, its purpose, the procedures involved, the potential risks and benefits, and their rights, including the right to withdraw from the study at any time without penalty.
 
[3] Privacy and Confidentiality: Ethical approval also ensures that the researchers have a plan in place to protect participant’s privacy and confidentiality. This is particularly important in RWE studies, where the data may come from various sensitive sources such as electronic health records, insurance claims databases, patient registries, and more.
 
[4] Avoidance of Bias: Ethics committees help ensure that the study is designed in a way that will minimize bias, increasing the validity of the results.
 
[5] Trustworthiness of the Research: By requiring ethical approval, journals are able to guarantee a certain level of quality control. Ethical approval can indicate that the research has been conducted appropriately and that the results are trustworthy.
 
[6] Compliance with International Standards: Ethical approval ensures that research is conducted in line with the globally recognized ethical guidelines and principles such as the Declaration of Helsinki e.g., the International Committee of Medical Journal Editors “Recommendations” (Link: https://lnkd.in/er-Sj5py). Also, according to the National Health Commission of China, when academic journals publish the results of human life science and medical research, they shall confirm that the research has been approved by the ethics review committee. Researchers should provide relevant proof (Article 29 of the 2023 Ethical Review Measures).
 
By requiring ethical approval, peer-reviewed journals ensure that the research they publish is ethical, credible, and respectful of participant rights. This is crucial in maintaining trust in the research community and the broader public who may ultimately benefit from the research findings.

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Real World Evidence (RWE) 101 – Publications2023-08-07T19:41:16+00:00

Real World Evidence (RWE) 101 – Archiving Specifics

RWE 101 – Archiving Specifics

Proper archiving of clinical study documents is an important practice for maintaining the quality, integrity, and usability of study data, and for ensuring regulatory compliance. These aspects are especially important in the context of RWE studies, where the scope and complexity of the regulatory requirements and standards, can differ significantly across and between regions. For example, here are some country-specific archiving timelines for observational drug studies:
 
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
 
According to ISPE GPP, 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.
 
Additional considerations when determining what to archive and for how long, include:
 
[1] Legal Protection (Contractual Obligations): Archiving documents can offer protection in the event of legal questions or disputes related to the conduct of the study, data ownership, patient consent, adverse event reporting, etc. If you are a vendor, check study management contracts for any document retention obligations.
 
[2] Real-World Study Document Index (RWS-DI): The RWS-DI is 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. 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.”
 
In conclusion, the process of archiving clinical study documents should not be overlooked, especially in the arena of RWE studies. Regulatory compliance, data validation, legal protection, and future research potential hinge on the effective preservation of these important materials. As the rules can differ wildly from Argentina’s 2-year requirement to Austria and Netherlands’ 15 years, it’s critical to be aware of both regional specifics and overarching guidelines like the ISPE GPP’s five-year rule. Additionally, tools like the RWS-DI provide a specialized framework to ensure that archiving practices are tailored to the unique needs of RWE studies. So, when you’re next managing an observational study, remember – good archiving isn’t just about meeting regulations; it’s about safeguarding the integrity of your study, its results, and the future studies it may inspire.

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Real World Evidence (RWE) 101 – Archiving Specifics2023-08-07T19:33:49+00:00

Real World Evidence (RWE) 101 – Archiving Generics

RWE 101 – Archiving Generics

In the context of health research, both observational studies and clinical trials are crucial for understanding disease processes, patient outcomes, and the safety and efficacy of treatments. However, due to varying regulatory requirements and standards, the archiving requirements for these types of studies are distinct. Here are some of the key differences:
 
[1] Regulations and Guidelines: Clinical trials as governed by a global set of ethical and scientific standards, such as ICH GCP. These standards are then adopted into law in different regions, say for instance, through the Regulation EU/536/2014, and 21 CFR 312 in the US. These rules are clear about how to manage, store, and archive data and require specific documents to prove the integrity of the trial data. They also set out how long these crucial documents should be kept (e.g., at least 25 years).
 
On the flip side, observational studies aren’t governed by such unified requirements when it comes to document retention and archiving. They still follow ethical guidelines and good practice principles like the Declaration of Helsinki, ISPE GPP, and STROBE guidelines, but these may not give you exact retention times or archiving mechanisms.
 
[2] Data Collection and Confidentiality: Clinical trials are data-rich; they collect a large amount of confidential and sensitive patient data. Regular sponsor audits and regulatory inspections mean they need to keep robust records. Observational studies, while they also handle sensitive data, usually don’t interact with patients as much and don’t face as many regulatory inspections. So, they’ve traditionally not had to maintain as meticulous records.
 
[3] Data Accessibility: Clinical trial data is often more restricted in terms of who can access it and how it can be shared. This is due to both regulatory needs and commercial interests. Observational data, though, is often used for big-picture disease studies, and it’s usually designed to be more shareable – as long as it’s anonymized and ethical procedures are followed.
 
It’s important to remember that what I’ve explained are general patterns. The exact requirements can change based on region, the type of data you’re dealing with, and even who’s funding your work. If you need specific guidance, don’t hesitate to reach out to an expert or regulatory authority in your area.

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Real World Evidence (RWE) 101 – Archiving Generics2023-08-07T18:44:26+00:00

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
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