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Real World Evidence (RWE) 201 – FDA’s Advancing RWE Program

RWE 201 – FDA’s Advancing RWE Program

Real-world evidence is transforming the regulatory landscape, enabling the FDA to make informed decisions based on robust data from real-world settings. In line with this, the FDA has launched the Advancing Real-World Evidence (RWE) Program, aiming to harness the benefits of RWD to support new labelling claims, expand indications for approved medical products, and fulfil post-approval study requirements.

Goals of the Program:

  1. Identify strategies for creating RWE that satisfies regulatory needs for labelling effectiveness or post-approval study obligations.
  2. Establish agency protocols for consistent RWE decision-making and shared knowledge.
  3. Encourage public understanding of RWE’s attributes for informed regulatory choices through public discussions.

Eligibility:

  1. Sponsors must have a pre-IND or IND number for their medical product
  2. The RWE proposal should aim at supporting labelling for effectiveness or meeting post-approval study demands
  3. Both FDA and sponsor must consent to publicly disclose the study design

Selection:

  1. The FDA welcomes all fitting RWE proposals. Selection is based on data’s suitability, study design quality, regulatory conduct, and diverse data sources and methodologies

Submission Process:

  1. Semi-annual submission deadlines: 31 March and 30 September, continuing until 31 March 2027
  2. Sponsors will be told whether their meeting request has been accepted within 45 days post-deadline. Successful applicants can apply for an additional 3 follow-up meetings.

Initial Meeting Request Content – Sponsors must provide:

  1. Product name
  2. IND number
  3. Study purpose (new labelling/post-approval study)
  4. Proposed indication
  5. Product development history
  6. Rationale for RWE approach
  7. Study design overview
  8. Non-disclosable design elements and reasons for their omission
  9. Study design details: objectives, design, eligibility, endpoints, treatment, comparator, concomitant therapies
  10. Data sources: category, description, validation, linkage, additional data collection.
  11. Analysis plan: sample size, analytic plan, confounding factors, follow-up period, data handling
  12. Other factors: study pre-specification, patient data availability, human subject protection

Disclosure Agreement:

Before initial meetings, FDA and sponsors decide on public data disclosure. Certain details, like sponsor name and patient data, are excluded from disclosure. However, unique disclosure considerations are allowed. Participation is voluntary.

In conclusion, the FDA’s Advancing RWE Program offers a structured approach for sponsors to collaborate with the FDA and harness the potential of RWE in label extensions and post market studies.

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Real World Evidence (RWE) 201 – FDA’s Advancing RWE Program2023-08-21T11:58:11+00:00

Real World Evidence (RWE) 201 – FDA’s RWE Considerations Draft Guidance

RWE 201 – FDA’s RWE Considerations Draft Guidance

The 21st Century Cures Act, signed into law in 2016, mandated the FDA to establish a framework for the evaluation of RWE in regulatory decision-making. This draft FDA guidance document forms part of the FDAs RWE program and addresses several key regulatory considerations for the use of RWE in regulatory decision-making. Let’s explore each of these considerations in more detail:

FDA Draft Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (Dec 2021): https://www.fda.gov/media/154714/download

[1] Applicability of 21 CFR Part 312: Interventional studies involving drugs generally meet the definition of a clinical investigation (clinical trial) and are subject to FDA regulations under 21 CFR Part 312. On the other hand, non-interventional studies analyse data reflecting the use of a marketed drug in routine medical practice, as such non-interventional studies are not clinical investigations as defined under 21 CFR 312.3 and do not require an investigational new drug application (IND).

[2] Early Engagement with the FDA: Transparency is essential in non-interventional studies to ensure the reliability of the data collected. Sponsors should engage with the FDA in the early stages of study design, provide draft versions of protocols and statistical analysis plans for review, and finalise these documents before conducting the study analyses.

[3] RWD Data Access: Sponsors should discuss with the FDA their expectations regarding access to RWD for their development program. They should ensure that patient-level data from RWD can be submitted to the FDA when required and have agreements in place with third-party data owners to provide relevant data for inspection.

[4] Study Monitoring: Study monitoring in non-interventional studies focuses on maintaining the reliability of RWD and data integrity. Sponsors should ensure that applicable human subject protection requirements are met (IRB approval and informed consent – 21 CFR 50 and 21 CFR 56) and consider a risk-based approach to study oversight.

[5] Safety Reporting: Adverse events identified during non-interventional studies must be reported to the FDA in accordance with postmarketing safety reporting regulations (21 CFR 314.80).

[6] Other Sponsor Responsibilities: Sponsors are responsible for various activities related to the design, conduct, and oversight of non-interventional studies. These activities include selecting qualified researchers, ensuring compliance with protocols and regulations (e.g., 21 CFR 11), maintaining study records, registering the study on clinicaltrials.gov, and providing access to relevant records upon request.

In summary, this FDA guidance document provides valuable insights into the considerations for leveraging RWE to support regulatory decisions. By adhering to the guidance and engaging with the FDA early in the study design process, industry stakeholders can effectively utilise RWE to enhance the safety and effectiveness evaluation of drugs and biological products.

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Real World Evidence (RWE) 201 – FDA’s RWE Considerations Draft Guidance2023-08-21T16:03:17+00:00

Real World Evidence 201 – FDAs RWE Framework

RWE 201 – FDAs RWE Framework

Real World Evidence (RWE) 201 – FDAs RWE Framework

RWE 201: https://rwr-regs.com/rwe-201/

The FDA’s Real-World Evidence (RWE) Program framework, established under the 21st Century Cures Act, focuses on several key aspects:

[1] Scope of RWE Program Under 21st Century Cures Act: The program aims to evaluate the potential use of RWE to support the approval of a new indication for a drug already approved under section 505(c) of the FD&C Act or to help support or satisfy drug post-approval study requirements (e.g., FDAs Advancing RWE Program).

[2] Current Use of Real-World Data (RWD) for Evidence Generation: RWD sources, such as electronic health records, medical claims, and billing data, can be used for data collection and to develop analysis infrastructure to support various study designs, including randomized clinical trials and observational studies.

Current Uses of RWE:

  • Complementing traditional clinical trial data.
  • Supporting post-market commitments or requirements.
  • Label expansions (e.g., adding new indications for approved drugs).
  • Observational studies to understand product safety and effectiveness.

[3] Generating Evidence Regarding Safety and Effectiveness: Historically, there has been limited use of RWE to support effectiveness. Advances in the availability and analysis of RWD have increased the potential for generating robust RWE to support FDA regulatory decisions.  However, the value of using RWE to support regulatory decisions on drug efficacy and effectiveness has yet to be established.  To be explored further when we move to the EU and the EMAs RWE 2025 Vision.

[4] Framework for Evaluating RWD/RWE for Use in Regulatory Decisions: The FDA’s framework for evaluating RWD and RWE involves assessing the fitness of RWD (sources) for use in regulatory decisions, potential for study designs using RWD to support effectiveness, and regulatory considerations for study designs using RWD.

Data Quality and Reliability:

  • Not all RWD is fit for regulatory decisions. The FDA assesses the relevance and reliability of RWD.
  • Sources of RWD must be transparent, and any transformations to derive RWE must be robust and valid.

Methodological Challenges:

  • There are inherent biases in RWD because they are observational in nature
  • FDA focuses on minimising biases and promoting the use of appropriate statistical methods.

The framework aims to facilitate the acceleration of medical product development and the delivery of medical innovations for patients in need. It also distinguishes between the sources of RWD and the evidence derived from that data, as evaluating RWE in the context of regulatory decision-making depends on the evaluation of the methodologies used to generate the evidence and the reliability and relevance of the underlying RWD.

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Real World Evidence 201 – FDAs RWE Framework2023-08-16T15:06:53+00:00

Real World Evidence (RWE) 101 – Real World Evidence (RWE) 101 – Audits vs Inspections

RWE 101 – Real World Evidence (RWE) 101 – Audits vs Inspections

In the context of regulatory compliance for Real-World Evidence (RWE), both audits and inspections play crucial roles, but they differ primarily in their purpose, scope, and the parties conducting them.

1. AUDIT: An audit is usually a more routine, self-regulated evaluation of the RWE processes and controls in place to ensure regulatory compliance, data quality, and data integrity. These audits may be performed by internal staff (internal audit) or by an external independent party (external audit). They focus on examining the documentation, systems, and procedures that are in place to ensure they are in compliance with regulatory standards, policies, and best practices. The ultimate goal of an audit is to provide assurance that the RWE produced is reliable, valid, and can be trusted for making health care decisions.

2. INSPECTION: An inspection is typically a more formal, structured examination conducted by regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Inspections often occur less frequently than audits and are usually more comprehensive and rigorous. They’re conducted to ensure that the data and processes being used comply with regulatory standards, guidelines, and laws. An inspection often focuses not only on compliance but also on enforcement, with potential consequences for significant non-compliance, including fines, penalties, and potentially barring the use of the collected RWE in regulatory decision-making.

In summary, while both audits and inspections aim to ensure regulatory compliance and high-quality, reliable RWE, audits are often more routine and self-directed evaluations, while inspections are formal evaluations conducted by regulatory bodies with an emphasis on compliance and enforcement.

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Real World Evidence (RWE) 101 – Real World Evidence (RWE) 101 – Audits vs Inspections2023-08-09T14:51:12+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 – 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 – 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 – Protocol Design and Scientific Best Practices

RWE 101 – Protocol Design and Scientific Best Practices

 

Designing a robust Real-World Evidence (RWE) study is crucial for generating reliable and valid insights that are acceptable to regulators. Here are some scientific best practices to consider according to regional drug regulatory authorities:
 
EUROPEAN UNION – According to the European Medicines Agency (EMA), relevant scientific guidance should be considered by marketing authorisation holders and investigators for the development of study protocols, the conduct of studies and the writing of study reports…These scientific guidelines include the:
1. ENCePP Guide on Methodological Standards in Pharmacoepidemiology
2. ENCePP Checklist for Study Protocols, and
3. Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP)
Ref: Section VIII.B.1. of GVP Module VIII
 
GERMANY – The observation plan is to be drawn up according to recognized recommendations of scientific or regulatory guidelines…for example:
1.  Guidelines for Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology (ISPE GPP),
2. Recommendations of the ” ENCePP Guide on Methodological Standards in Pharmacoepidemiology”, and
3. Guidelines for Good Epidemiological Practice (GEP) of the German Society for
Epidemiology (DGEpi)
Ref:  Section 2.7.1 of the BfArM/PEI Recommendations – December 2022
 
CANADA – All research protocols should be well-designed and include a comprehensive assessment of good research principles. There are fifteen key elements that should be considered for each protocol, and are reflective of the:
1. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Protocol Checklist, and
2. The Guidelines for Good Pharmacoepidemiology Practices (GPP).
Both prospective and retrospective designs should attempt to address each element, or provide justification why it may not be applicable to the specific study.
Ref: Health Canada – Elements of Real World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle, March 2019
 
USA – According to the FDA’s “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data” of May 2013, the following provide general guidance applicable to all pharmacoepidemiologic safety studies:
1. ISPE guidelines (ISPE GPP),
2. STROBE reporting framework, and
3. The ENCePP methods checklist
Ref: FDA Guidance – Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data
 
These scientific best practices will help ensure that the RWE study is robust, credible, and provides meaningful information to patients, healthcare providers, and policy makers.

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Real World Evidence (RWE) 101 – Protocol Design and Scientific Best Practices2023-08-07T16:51:55+00:00

Real World Evidence (RWE) 101 – Study Designs

RWE 101 – Study Designs

Real-world evidence (RWE) studies are becoming increasingly important in healthcare decision-making. There are various study designs used to generate RWE, each with their unique benefits:
 
[1] Cohort Studies: Cohort studies are observational in nature, where two or more groups (cohorts) distinguished by their exposure to a certain factor (like a medical treatment or lifestyle choice) are followed and assessed to determine the effect of that exposure. These studies are advantageous in studying rare outcomes, multiple outcomes, or outcomes that take a long time to develop.
 
[2] Case-Control Studies: These studies start with the outcome and then look backward to find the exposure. They’re efficient for studying rare diseases or diseases with a long latency period, as well as multiple exposures. However, they may not be as reliable as cohort studies due to potential recall bias.
 
[3] Cross-Sectional Studies (Prevalence Studies): These studies observe a defined population at a single point in time or time interval. They’re useful in understanding the burden of a disease in a population, assessing public health needs, and planning healthcare services.
 
[4] Registry-Based Studies: These are observational studies where data are collected prospectively or retrospectively for patients with a particular condition or who are undergoing a specific procedure. Registry-based studies provide long-term, real-life data about prognosis, adverse events, quality of life, and cost-effectiveness.
 
[5] Pragmatic Clinical Trials (PCTs): Unlike traditional randomized clinical trials, PCTs are designed to determine the effectiveness of interventions in real-world routine practice conditions. They often include a more diverse patient population, multiple care settings, and less rigid protocols.
 
[6] Retrospective Studies: This involves analyzing existing datasets (like EHRs or insurance claims databases) to find associations or trends. This is also known as secondary use of existing data. While these are generally quicker and less expensive, they are subject to the limitations of the existing data, which may not have been collected for research purposes.
 
[7] Prospective Observational Studies: In these studies, subjects are followed over time with data collected about various factors that might influence the outcome of interest. These studies are useful in understanding the natural history of disease and the effectiveness of different treatments in the real world. These studies usually include both secondary data (data collected for a different purpose) and primary data (data collected specifically for the purposes of the study).

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Real World Evidence (RWE) 101 – Study Designs2023-08-07T16:44:52+00:00

Real World Evidence (RWE) 101 – Protocol Considerations

RWE 101 – Protocol Considerations

Real-world evidence (RWE) study protocols and clinical trial protocols both outline the design and conduct of a study. However, they are distinctly different in several ways given the differences in objectives, methodologies, settings, and populations involved in clinical trials versus RWE studies.
 
[1] Objectives: The main objective of a clinical trial is to evaluate the efficacy and safety of a medical intervention in a controlled environment, usually by comparing it to a placebo or standard treatment. On the other hand, RWE studies typically aim to understand how an intervention works in routine clinical practice, often focusing on outcomes such as long-term effectiveness, side-effects, quality of life, and cost-effectiveness.
 
[2] Study Design and Methodology: Clinical trials, especially phase III, are predominantly randomized controlled trials (RCTs) where subjects are randomly assigned to the intervention or control group to minimize bias. They follow a pre-specified protocol and are conducted under tightly controlled conditions. RWE studies, on the other hand, are typically observational in nature and analyze data from sources like electronic health records (EHRs), claims databases, or patient registries.
 
[3] Setting: Clinical trials are conducted in specific, controlled environments and follow a strict protocol. RWE studies are conducted in routine clinical practice settings, making them more representative of ‘real-world’ conditions.
 
[4] Population: Clinical trials often have strict inclusion and exclusion criteria, resulting in a relatively homogeneous group of participants. This can limit the generalizability of the results. RWE studies, in contrast, involve broader, more diverse populations (including those often excluded from trials like the elderly, people with multiple co-morbidities, etc.), making the findings more generalizable to everyday practice.
 
[5] Data Collection: In clinical trials, data collection is rigorous, detailed, and specific to the trial endpoints. Adverse events are actively sought and documented. RWE studies primarily rely on existing data sources such as EHRs, patient registries, or insurance claims data. This can potentially lead to incomplete or inaccurate data.
 
[6] Intervention: In clinical trials, the intervention (dosage, frequency, duration, etc.) is pre-specified and strictly monitored. In RWE studies, interventions reflect routine clinical practice and may vary widely.
 
[7] Follow-up: Clinical trials have a defined follow-up period while RWE studies can often provide information on long-term outcomes, given they use data from routine clinical practice over longer periods.
 
While clinical trials provide the highest level of evidence for determining a treatment’s efficacy, RWE studies complement this by providing evidence on real-world effectiveness and long-term safety.

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Real World Evidence (RWE) 101 – Protocol Considerations2023-08-07T16:38:31+00:00
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