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Real World Evidence (RWE) 201 – FDA’s RWE Considerations Draft Guidance

RWE 201 – FDA’s RWE Considerations Draft Guidance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FDA Draft Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (Dec 2021):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 201 – The 21st Century Cures Act

RWE 201 – The 21st Century Cures Act

The 21st Century Cures Act (CURES 1.0), signed into law in the U.S. in December 2016, aimed to accelerate medical product development and foster innovation and advances in patient care. One of the key aspects of the Act is its focus on utilizing Real-World Evidence (RWE), transforming the way healthcare providers approach patient care and medical research.

RWE refers to data collected from various sources outside of traditional clinical trials, such as Electronic Health Records (EHR), claims and billing data, patient registries, and patient-generated data. The 21st Century Cures Act recognizes the importance of RWE in improving the efficiency of the drug development process by supporting its use in the approval of new indications for approved drugs, as well as satisfying post-approval study requirements (i.e., PMCs and PMRs).

By leveraging RWE, the FDA can make regulatory decisions using more diverse and inclusive patient data, reflecting a broader patient population and potentially leading to more personalized and effective treatments. It also has the potential to reduce costs and time needed for traditional trials, accelerating the availability of life-saving drugs.

Critics of using RWE in regulatory decisions cite concerns about data quality, reliability, and potential biases. To address these concerns, the FDA has been working to develop guidance and standards for collecting and evaluating RWE, which we’ll explore later.

The 21st Century Cures Act encourages the use of real-world evidence (RWE) in regulatory decision-making in several ways:

[1] Developing an RWE Framework and Guidance: The Cures Act required the FDA to develop a framework and guidance for evaluating RWE in the context of regulating drugs and biologics. This helps support approvals of new indications for previously approved drugs and fulfil post-approval study requirements.

[2] Promoting the Use of RWE in Regulatory Decisions: The Act places additional focus on using RWE to support regulatory decision-making, such as approving new indications for medical devices without requiring new clinical trials.

[3] Modernizing Clinical Trial Designs: The Cures Act supports the modernization of clinical trial designs, including the use of RWE and clinical outcome assessments, which can lead to more efficient clinical trials and faster access to new treatments for patients.

In summary, the 21st Century Cures Act’s emphasis on RWE signifies a shift towards a more modern and flexible approach to medical product development. It fosters collaboration between regulatory agencies, healthcare providers, and industry to utilize real-world data in improving patient outcomes, speeding up innovation, and enhancing the efficiency of healthcare delivery.

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Real World Evidence 201 – The 21st Century Cures Act2023-08-16T14:54:57+00:00

Real World Evidence (RWE) 101 – ICH GCP (R3) – Real World Evidence Context

RWE 101 – ICH GCP (R3) – Real World Evidence Context

Revision 2 of ICH GCP caused confusion to those of us who work with non-interventional studies. The glossary claimed that a ‘clinical trial’ was synonymous with a ‘clinical study’ (Section 1.12 of ICH GCP(R2)). This works if you conduct clinical trials (they are a type of clinical study), but not if you conduct non-interventional studies, which are a type of ‘clinical study other than a clinical trial’ (Article 2.2(4) of Regulation EU/536/2014).

The (draft) Revision 3 of ICH GCP, makes it clear “This guideline applies to interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities. This guideline may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorisation applications in accordance with local requirements.”

Also, the new definition of ‘clinical trial’ provided in the Glossary, removes any confusion regarding clinical trial vs clinical study.

Clinical Trial = Any interventional investigation in human participants intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

The emphasis in ICH GCP(R3) is on ‘interventional’ investigations, although the term ‘intervention’ is missing from the Glossary…as well as most national clinical trial regulations. This may cause trialists some difficulties in the coming years when asked ‘what makes my non-interventional study…interventional?’

This revision to the clinical trial definition and explicit emphasis on ‘interventional clinical trials’ is a positive (constructive) move in the context of real world evidence as it removes the previously unnecessary confusion caused by revision 2 (i.e., clinical trial = clinical study).

The concept paper for Annex 2 was published on 28 April 2023, with the draft expected in 12 – 18 months. Annex 2 is of relevance to RWE because it will include additional considerations on how GCP principles may be applied across a variety of trial designs and data sources, where applicable. This will include:

1. Decentralised elements, where some or all trial-related activities occur at locations other than traditional clinical trial sites, and data collection may occur remotely.

2. Pragmatic elements, reflecting trials that closely resemble routine clinical practice.

3. Real-world data (RWD) sources [not including observational studies], for example, the use of registries, electronic health records (EHR), hospital data, pharmacy and medical claims data or wearables

Next? Is it time for similar harmonised guidelines for ‘non-interventional studies’?

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Real World Evidence (RWE) 101 – ICH GCP (R3) – Real World Evidence Context2023-08-09T15:27:28+00:00

Real World Evidence (RWE) 101 – Non-Interventional Studies vs Market Health Research

RWE 101 – Non-Interventional Studies vs Market Health Research

Key differences between a non-interventional study (NIS) and market health research include:

1. Research Objective: NIS are conducted to examine real-world data and generate evidence on the effectiveness, safety, and outcomes of healthcare interventions in clinical settings. Market health research focuses on understanding market dynamics, consumer behavior, and market trends related to healthcare products or services.

3. Participants: NIS involve patients, healthcare providers, or healthcare institutions as participants, with the goal of studying healthcare interventions and their impact. Market health research focuses on consumers, stakeholders, and market entities, aiming to understand their preferences, attitudes, and behaviors related to healthcare products or services.

4. Methodology: NIS employ observational study designs, analyzing existing data or prospectively collecting data without actively intervening or manipulating variables. Market health research typically involves surveys, interviews, focus groups, or other market research techniques to gather specific information from targeted populations or market segments.

5. Data Collection: NIS gather clinical and patient-related data, such as treatment outcomes, adverse events, medical records, or registries, to assess the real-world impact of healthcare interventions. Market health research collects data on consumer perceptions, attitudes, preferences, purchasing behaviors, or market trends related to healthcare products or services.

6. Ethical Considerations: NIS are subject to research ethics guidelines and regulations, ensuring participant privacy, informed consent, and data confidentiality. Market health research also follows ethical guidelines, focusing on obtaining voluntary participation, ensuring data privacy, and protecting personal information.

7. Stakeholders: NIS primarily involve healthcare providers, researchers, and patients, aiming to inform clinical decision-making and healthcare policies. Market health research involves a broader range of stakeholders, including consumers, healthcare organizations, manufacturers, payers, and policymakers, with the goal of informing marketing strategies, product development, or policy decisions.

8. Reporting and Dissemination: NIS findings are typically reported in scientific journals, presented at medical conferences, or used to inform healthcare guidelines and policies. Market health research findings are often shared through market research reports, industry publications, or utilized internally for strategic decision-making within organizations.

While non-interventional studies and market health research have different objectives and methodologies, they can complement each other by providing a comprehensive understanding of healthcare interventions, their real-world impact, and the market dynamics surrounding healthcare products and services.

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Real World Evidence (RWE) 101 – Non-Interventional Studies vs Market Health Research2023-08-09T15:02:58+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 – A Career of Many Pathways

RWE 101 – A Career of Many Pathways

Real-world evidence (RWE) refers to the information on health care that is derived from analysis of real-world data (RWD). RWE is increasingly used in health care decisions.

The career path to get into RWE is not set in stone, as it involves a combination of skills from different disciplines such as epidemiology, biostatistics, public health, computer science, and data analysis. However, below are some usual steps that individuals may follow:

[1] Education: This typically involves obtaining a Bachelor’s degree in a relevant field such as biology, public health, epidemiology, or statistics. A Master’s degree or a Ph.D. in a related field such as epidemiology, biostatistics, public health, or health economics is highly valuable. Also, acquiring knowledge in the field of data science or bioinformatics could be beneficial.

[2] Entry-Level Experience: This could be roles in clinical research, health services research, or other types of medical or public health research. This might also involve experience in data analysis or management, particularly with healthcare datasets.

[3] Mid-Level Experience: As one gains experience, they may start to specialize in areas related to RWE. This could involve roles in health economics and outcomes research (HEOR), pharmacovigilance, or clinical epidemiology.

[4] Advanced-Level Experience: Eventually, they may move into roles that directly involve the generation, analysis, or interpretation of RWE. This could be in a pharmaceutical company, a consulting firm, a healthcare provider, or a public health agency.

[5] Continuous Learning: As the field of RWE evolves rapidly with the development of new methodologies and data sources, continuous learning is essential. This could involve regular participation in professional development opportunities and staying current with the scientific literature.

It’s important to remember that this is just a general path, and many individuals may take different routes into RWE, leveraging their unique skills and experiences. For instance, some might come from a medical background, using their clinical knowledge to help shape and interpret RWE studies. Others might come from a more traditional epidemiology or public health background, applying those skills to the analysis of RWE. Some may even come from a data science or bioinformatics background, using their skills to manage and analyse large, complex healthcare datasets.

RWE is a dynamic and interdisciplinary field, so there are many pathways into it. It’s all about finding the intersection of your skills and interests with the needs of the field

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Real World Evidence (RWE) 101 – A Career of Many Pathways2023-08-07T22:28:44+00:00

Real World Evidence (RWE) 101 – Evolution of Regulatory Affairs

RWE 101 – Evolution of Regulatory Affairs

Real-world evidence (RWE) and real-world data (RWD) are increasingly influencing regulatory affairs in the biopharmaceutical and healthcare industry. This change has been brought about due to the recognition of the value of real-world data in assessing the safety, efficacy, and effectiveness of therapies beyond traditional clinical trials.
 
[1] Increased Importance of Post-Marketing Surveillance: With RWE, regulatory agencies now have increased access to post-marketing surveillance data. This data is helping in better identification of adverse events and monitoring the safety of products in the market.
 
[2] Regulatory Decision Making: RWE is becoming increasingly significant in regulatory decision-making, including label extensions, post-approval studies requirements, and in some cases, approval decisions themselves. Regulatory bodies such as the FDA and EMA are now considering RWE as part of their evidence package, though with caution and scrutiny.
 
[3] Guidelines and Policies: Regulatory bodies are developing guidelines for the use of RWE in regulatory decision-making. The FDA, for instance, has issued guidance on the use of RWE to support approval of new indications for already approved drugs or to satisfy post-approval study requirements.
 
[4] Innovative Trial Design: The increased use of RWE is promoting the use of innovative clinical trial designs like pragmatic clinical trials (PCTs), which make use of real-world data.
 
[5] Technology and Data Privacy Considerations: With RWE coming largely from electronic health records, insurance claims data, and wearables, regulatory affairs, especially study start-up professionals, will need to grapple with data privacy and cybersecurity issues. There’s an increasing need for regulations that guide the use and protection of such data.
 
[6] International Harmonization: As RWE can be collected globally, there are efforts to harmonize the guidelines across different countries to make multinational studies feasible.
 
[7] Transparency and Trust: Ensuring the validity and reliability of RWE studies is a growing concern. This has led to an increased focus on transparency in data collection, analysis methods, and reporting, all of which regulatory affairs must oversee, especially in the context pf RWE used for regulatory submissions, such as marketing authorisations..
 
Thus, the intersection of RWE and regulatory affairs is evolving and holds potential for improving healthcare decisions and outcomes. Regulatory affairs professionals must adapt to these changes, requiring new skills and competencies in data analysis and understanding of the evolving regulatory landscape for RWE.

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Real World Evidence (RWE) 101 – Evolution of Regulatory Affairs2023-08-07T22:02:40+00:00

Real World Evidence (RWE) 101 – Project Managers

RWE 101 – Project Managers

Real-World Evidence (RWE) observational studies and clinical trials are both key elements of medical research, but they involve very different methodologies, aims, and requirements. As a result, the role of a project manager in each type of study will differ significantly.
 
Here’s a high-level overview of how the role of a project manager differs for RWE observational studies versus clinical trials:
 
[1] Study Design and Execution: In RWE studies, the project manager has to deal with more varied and unpredictable study designs since these studies often rely on data that is collected during routine clinical practice. This role requires a higher degree of flexibility and the ability to adjust study plans and analysis methods as new data becomes available.
 
[2] Regulatory Compliance: Clinical trial project managers have to comply with strict regulations based on guidelines such as Good Clinical Practice (GCP). Whereas, the regulatory landscape for RWE studies is more varied, with guidelines and norms often differing by data source and locality. However, RWE studies are increasingly being used in regulatory decision-making, so there is a growing focus on maintaining data quality and ensuring appropriate use of data.
 
[3] Data Management: In clinical trials, project managers oversee data is gathered in a very structured way with predefined data points. Project managers in RWE studies deal with large, real-world data sets that can come from a variety of sources, like electronic health records (EHRs), insurance claims data, or patient registries. They have to manage complex, unstructured data and may have to deal with issues related to data cleaning, missing data, or data integration.
 
[4] Stakeholder Engagement: Project managers for clinical trials and observational studies must coordinate with a variety of stakeholders, including clinicians, patients, sponsors, regulatory bodies, and ethics committees. They have to manage patient recruitment and retention, monitor trial progress, and handle any issues that arise during the trial.
 
[5] Analysis and Reporting: For both clinical trials and observational studies project managers play a crucial role in ensuring that analysis is conducted as per the pre-specified statistical analysis plan and results are reported in a standardized format. Project managers overseeing RWE studies have to navigate more complex and varied analysis strategies due to the nature of the data. They may also have to engage more with stakeholders to communicate findings and their implications, and reporting may be more tailored to the needs of specific stakeholders.
 
In both types of studies, the project manager is responsible for ensuring the project is delivered on time, within budget, and to a high standard of quality. However, the specifics of what this involves can vary considerably depending on whether the study is a clinical trial or an RWE observational study.

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Real World Evidence (RWE) 101 – Project Managers2023-08-07T21:50:20+00:00

Real World Evidence (RWE) 101 – Ethical Imperatives (CIOMS 2023)

RWE 101 – Ethical Imperatives (CIOMS 2023)

Informed decision making with patients typically relies on evidence from clinical trials that describe the likely benefits and toxicities. However, patients treated in everyday practice tend to be older and more frail, to have poorer function and performance status, and to have more comorbidities and less social support than those selected to participate in clinical trials. Thus, generalisability to typical patient populations treated in daily practice is often limited. Kennedy-Martin et al explored the generalisability of RCTs in cardiology, mental health, and oncology by assessing studies comparing participants in such trials with those in everyday clinical practice. Patients treated in everyday clinical practice tended to be older, were more often women, and had more comorbidities; 71% of studies concluded explicitly that RCTs were not broadly representative of real-world patients, in particular, pregnant and lactating women are a very large population that is often entirely unrepresented in clinical trials. Furthermore, patients enrolled in trials were treated according to guidelines more often and received more in-hospital procedures. Strict selection criteria for RCTs meant that participants were at a much lower risk of adverse events compared with patients treated in clinical practice.
 
If the efficacy-effectiveness gap means that patients are being given inaccurate information about the potential benefits and risks of treatments, then decisions made using that information may be being made without valid informed consent, disrespecting patient’s autonomy and putting them at risk of avoidable harm. The efficacy-effectiveness gap also raises important issues regarding justice; if resource allocation decisions, including which treatments are funded, are made using evidence that is biased by the efficacy-effectiveness gap, then those decisions will also be flawed, with potentially wide implications for patients. Ultimately, the efficacy-effectiveness gap undermines the gold standard status of RCTs, and actually suggests that it would be unethical to continue with such a flawed representation of real-world effects on patients. Increasing use of RWE is one important way to fill the efficacy-effectiveness gap and augment the evidence from RCTs. This should not be seen as dropping the gold standard, or diminishing the standard of evidence required; rather, enhancing and supplanting RCT evidence with RWD can instead be viewed as reinforcing the gold standard with platinum plating.
 
Source: Section 4.2 (Ethical arguments for incorporating more RWE) of the CIOMS Draft Guidance – Real-World Data and Real-World Evidence in Regulatory Decision Making (6 June 2023)

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Real World Evidence (RWE) 101 – Ethical Imperatives (CIOMS 2023)2023-08-07T21:46:07+00:00
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