USA | Draft FDA Guidance – Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products GalleryUSA | Draft FDA Guidance – Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products
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Real World Evidence (RWE) 201 – A Tale of Two Regulatory Paths: Non-Interventional Studies in the USA
RWE 201 – A Tale of Two Regulatory Paths: Non-Interventional Studies in the USA
Non-interventional studies are different from randomized controlled trials (RCTs). Instead of actively intervening in a patient’s healthcare, researchers just observe and record what happens naturally during the patients normal (routine) healthcare journey. The data from these studies is useful because it helps generate ideas for further research, flag potential safety concerns, or even provide additional evidence for regulatory decisions, like updating product labels or expanding the use of approved medical products.
Now, if you’re thinking of submitting this data to the FDA, there are certain regulations (rules) you must follow. In the U.S., there are two main pathways:
[1] For studies that will be submitted to the FDA: There’s a ‘checklist’ to follow, such as complying with certain sections of the Code of Federal Regulations (21 CFR 11, 21 CFR 50, 21 CFR 56, etc.) and listing your study on public databases like clinicaltrials.gov.
[2] For studies that won’t be submitted to the FDA: The requirements are a bit different, focusing more on the Common Rule (45 CFR 46), but still following similar safety rules, such as 21 CFR 314 (drugs) and 21 CFR 600 (biologics).
Despite the differences, there are common themes between the two. Both need ethical green lights in the form of Institutional Review Board (IRB) approvals, and participant informed consent is a must. With health data involved, ensuring privacy is non-negotiable, meaning regulations like HIPAA come into play. And regardless of the regulatory pathway, the study should be well-designed and use rigorous methodology to ensure data quality, integrity, and reliability. This includes clear definitions of exposures, outcomes, confounders, and other variables.
Because it’s hard to predict if non-interventional study’s results (RWE) might be submitted to the FDA, it’s a good idea to play it safe and align with FDA regulatory requirements and guidelines from the start.
In both cases, it’s essential to follow good epidemiological and statistical practices to ensure that the findings are robust, valid, and interpretable. Non-interventional studies, by their nature, are more susceptible to confounding and bias than RCTs, so it’s crucial to apply methods that address or mitigate these potential pitfalls.
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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:
- Identify strategies for creating RWE that satisfies regulatory needs for labelling effectiveness or post-approval study obligations.
- Establish agency protocols for consistent RWE decision-making and shared knowledge.
- Encourage public understanding of RWE’s attributes for informed regulatory choices through public discussions.
Eligibility:
- Sponsors must have a pre-IND or IND number for their medical product
- The RWE proposal should aim at supporting labelling for effectiveness or meeting post-approval study demands
- Both FDA and sponsor must consent to publicly disclose the study design
Selection:
- 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:
- Semi-annual submission deadlines: 31 March and 30 September, continuing until 31 March 2027
- 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:
- Product name
- IND number
- Study purpose (new labelling/post-approval study)
- Proposed indication
- Product development history
- Rationale for RWE approach
- Study design overview
- Non-disclosable design elements and reasons for their omission
- Study design details: objectives, design, eligibility, endpoints, treatment, comparator, concomitant therapies
- Data sources: category, description, validation, linkage, additional data collection.
- Analysis plan: sample size, analytic plan, confounding factors, follow-up period, data handling
- 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 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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