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How to Integrate Real-World Evidence into Regulatory Submissions
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Appraising Medical Studies for Legal Research: Identifying Valid and Reliable Evidence
Dr.Nancy | Clinical and Medical Research Expert
03 Apr, 2025
Dr.Nancy | Clinical and Medical Research Expert
03 Apr, 2025
Introduction
Published on April, 2025
Submitting a manuscript to a journal requires extensive formatting network guidelines, which ensure the manuscript is intended such that clarity, consistency, and editorial policies are observed. Journals observe rigorous standards for scientific content, and they also uphold rigorous standards for presentation, structure and formatting of content. A properly formatted manuscript facilitates the review processes and develops the presentation of the work from a readable and professional standpoint, and by presenting the developed work in this way, it helps develop a positive first impression with those who will make the initial judgments on the document including editors and reviewers. From the title page to references and any supplementary materials; every aspect of an academic engagement requires precise formatting.
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How to Integrate Real-World Evidence into Regulatory Submissions
Introduction
Real-world evidence (RWE) is increasingly gaining traction with regulatory agencies around the globe as an important part of the drug and device development lifecycle. Regulatory submissions are no longer reliant solely on randomized controlled trials (RCT); for example, real-world data is being used to support label extensions, post-marketing requirements, and even primary evidence in rare or difficult-to-study conditions [1].
This article will help you with how to use RWE in regulatory files, including helpful advice and examples, along with insight into what agencies expect.
Understanding RWE and Its Role in Regulatory Submissions
Real-World Evidence (RWE) is clinical evidence on the use of, and potential benefits or risks associated with, a medical product based on the analysis of Real-World Data (RWD) [2].
The most common types of RWD include:
- Electronic Health Records (EHRs)
- Claims and billing records for medical billing
- Patient registries
- Health apps or wearable devices
- Pharmacy and laboratory records.
For example: EHR data from a national diabetes registry is used to measure long-term cardiovascular outcomes for a glucose-lowering therapy.
RWE is particularly useful:
- When randomization is unethical, impractical, or impossible.
- When there is a need for additional evidence for label expansions.
- When observational data can augment clinical data [4].
Regulatory Acceptance of RWE
International health organizations have recognized the importance of RWE, and provided a framework and guidance documents for how they will use it, as seen below:
| Regulatory Agency | Applicable Guidance | Approach |
| FDA (United States) | Real-World Evidence Framework, 21st Century Cures Act (2018) | To supplement regulatory decisions including approvals and new indications |
| EMA (European Union) | DARWIN EU Initiative, Big Data Task Force Documents | To promote its use in measuring effectiveness and safety |
| MHRA (United Kingdom) | Innovative Licensing and Access Pathway (ILAP) | To encourage submissions for early access utilizing RWE [3] |
Example – For the latest guidance documents written for your region before submission
Step-by-Step Guide to Integrating RWE
1. Determine the Submissions Purpose for RWE
Decide why RWE is incorporated. Examples include:
- Label extension support (e.g., new population or indication
- Contribution of real-world safety data
- Comparative arm
- Post authorization safety/efficacy requirement
Example: A pharmaceutical company uses registry data to show treatment adherence and real-world effectiveness of an asthma inhaler in children.
2. Evaluate the Quality of RWD
Before applying RWD, first assess relevance and reliability.
| Data Quality Factor | Definition | Key Questions |
| Completeness | Are all relevant variables included? | Are outcome measures included? |
| Accuracy | Is the data verified and coded as intended? | Are miscoding or erroneous entry a possibility? |
| Timeliness | Is the data accurate and current? | Is the timeframe relevant to your submission? |
| Representativeness | Is it representative of the population from which you plan to conduct the study? | Are there demographic or geographic biases present? |
Regulatory Note: Submissions must include references to the data source, how it was collected, along with any transformations or linkage processes.
3. Select an Appropriate Study Design
When you select your study design, this may influence the strength of your RWE. Common design types include:
- Retrospective cohort studies
- Case-control studies
- Prospective observational studies
- Synthetic/external control arms
- Pragmatic clinical trials [4]
For example, a treatment for a rare cancer uses an external control arm that is created from EHR data of historical patients, because ethical concerns make it impossible to randomize any patients to placebo.
Please include diagrams or flow charts in your submission to represent study design and patient selection in a visual manner.
4. Develop a Transparent and Robust Analysis Plan
Transparency is essential in the regulatory submission. Include:
- Well-defined endpoints with time windows
- Description of inclusion/exclusion criteria
- Rate-adjustment approaches (e.g., propensity score matching)
- Sensitivity and subgroup analyses
- Description of statistical software and programming codes [5]
Pro Tip: It may be helpful to submit a pre-specified protocol and Statistical Analysis Plan (SAP) as appendices.
5. Map RWE to the CTD Format
Meaningfully incorporate RWE results into the Common Technical Document (CTD) format.
| CTD Module | Components |
| 2.5 (Clinical Overview) | Summary Lon RWE rationale, RWE sources, RWE implications |
| 2.7 (Clinical Summary) | Complete descriptions of methodology and interpretation |
| 5.3.5 (Post-Marketing Experience) | Complete reports of RWE studies; safety data |
| 5.3.5 (Post-Marketing Experience) | Complete reports of RWE studies; safety data |
| 5.3.6 (Other Clinical Study Reports) | Observational studies or external comparator analyses |
Case Example: Real-World Evidence Supporting a Label Expansion
Product: Ibrance (palbociclib)
Indication: Breast cancer in men
Data Source: Flatiron Health electronic health records
Outcome: FDA accepted RWE as supportive information for label expansion; the data were remarkably consistent with previous trial data.
This example shows that RWE doesn’t need to be stand-alone; it can support the findings of clinical trials and provide compelling data for underrepresented populations
Common Pitfalls and How to Avoid Them
- Poor documentation: Always have document and provide data lineage and analytical code.
- Overreliance on RWE: Always use it as supportive evidence unless the RWE is otherwise accepted.
- Non-disclosure: Regulators prefer it when you explicitly state the limitations and biases, then not mentioned at all [6].
- Poor statistical methods: If you are using complex modelling approaches make sure you report clearly and justify those methods.
Best Practices for Regulatory Writers
- Utilize situations where you can collaborate or share ideas early on with statisticians, epidemiologists, and regulatory strategists
- Develop RWE-specific writing templates and checklists.
- Follow terminology and structure that aligns with ICH guidelines and regional agencies.
- Where possible, use visuals to present your data (e.g., Kaplan-Meier curves, patient flowcharts).
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Conclusion
Integrating Real-World Evidence into regulatory submissions is not or an option anymore it is becoming in many areas, a regulatory expectation. When planned properly and executed with rigor, transparency, and scientific robustness, RWE can supplement traditional clinical trial evidence gaps with alternative subjective evidence and potentially speed up access to therapies. As a regulatory writer, you have an obligation to prepare and articulate RWE in a clear, accurate, and useable context for regulatory purposes.
Remember, RWE is not a shortcut. It is a tool – when utilized appropriately RWE can be used to describe and articulate a further level of depth, relevance, and real-world contextuality into your regulatory applications.
References
- Multi-stakeholder workshop on Real World Data (RWD) quality and Real World Evidence (RWE) use | European Medicines Agency (europa.eu)on June 26, 2023, as well as DIA Innovating Clinical Trials in Europe meeting on November 15, 2023.
- The US Food and Drug Administration Sentinel System: a national resource for a learning health system, Journal of the American Medical Informatics Association, Volume 29, Issue 12, December 2022, Pages 2191–2200, https://doi.org/10.1093/jamia/ocac153
- Lau, C., Jamali, F., & Loebenberg, R. . (2022). Health Canada Usage of Real-World Evidence (RWE): Real-World Evidence used by Health Canada in Regulatory Decision Making. Journal of Pharmacy & Pharmaceutical Sciences, 25, 22236https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/32715
- Rebecca A. Miksad, Real‐World Evidence in Regulatory Decision Making: Time for Evidence Integration, Clinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics Clinical Pharmacology & Therapeutics, 1002/cpt.3444, 116, 5, (1153-1155), (2024).
- Miksad RA, Ryals CA. The US Food and Drug Administration Dual Mandate for Rapid Drug Review and Equity. JAMA Netw Open.2024;7(5): e2411447. doi:10.1001/jamanetworkopen.2024.11447
- Song F, Zang C, Ma X, Hu S, Sun Q, Chow SC, Sun H. The use of real-world data/evidence in regulatory submissions. Contemp Clin Trials. 2021 Oct; 109:106521. doi: 10.1016/j.cct.2021.106521. Epub 2021 Jul 31. PMID: 34339865.