var _paq = window._paq = window._paq || []; /* tracker methods like "setCustomDimension" should be called before "trackPageView" */ _paq.push(['trackPageView']); _paq.push(['enableLinkTracking']); (function() { var u=""; _paq.push(['setTrackerUrl', u+'matomo.php']); _paq.push(['setSiteId', '1']); var d=document, g=d.createElement('script'), s=d.getElementsByTagName('script')[0]; g.async=true;'//'; s.parentNode.insertBefore(g,s); })();

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

[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.

Share this story...

Real World Evidence (RWE) 201 – A Tale of Two Regulatory Paths: Non-Interventional Studies in the USA2023-08-20T15:40:46+00:00

Real World Evidence (RWE) 101 – Why Should Non-Interventional Studies NOT be Promotional?

RWE 101 – Why Should Non-Interventional Studies NOT be Promotional?

Non-interventional studies (NIS) are designed to observe and analyze data from real-world clinical settings without intervening or manipulating any variables. These studies play a crucial role in generating real-world evidence (RWE) and are important for understanding the effectiveness, safety, and outcomes associated with various healthcare interventions. Here are a few reasons why NIS should not be promotional:

1. Scientific integrity: The primary purpose of NIS is to gather unbiased and objective data to answer research questions or explore hypotheses. If these studies are conducted with a promotional intent, it can compromise the scientific integrity of the research. The results may be influenced or biased, leading to misleading interpretations and potentially affecting patient care.

2. Patient safety: NIS involve collecting data from patients in routine clinical practice. If these studies are conducted with a promotional motive, there is a risk of prioritizing the promotion of a product over ensuring patient safety. Patient well-being should always be the foremost concern in research, and any attempt to manipulate or skew the data for promotional purposes undermines this ethical principle.

3. Transparency and trust: NIS should be conducted with transparency and should provide reliable and unbiased evidence. When these studies are used as promotional tools, it can erode trust in the research process and industry. Maintaining public trust is crucial for the advancement of healthcare and the ethical conduct of research.

4. Conflicts of interest: If non-interventional studies are conducted for promotional purposes, it raises concerns about potential conflicts of interest. Researchers or organizations conducting the study may have financial or other vested interests in promoting a particular product. Such conflicts can compromise the objectivity and independence of the research and may lead to biased reporting and selective publication of results.

5. Regulatory considerations: Regulatory authorities often require non-interventional studies to provide robust and unbiased data to inform decision-making about the safety and effectiveness of medical products. If these studies are promotional in nature, it can undermine the credibility of the regulatory process and lead to inappropriate approvals or recommendations based on biased evidence.

To ensure the ethical conduct of NIS, it is essential to separate research activities from promotional activities. Clear guidelines and regulations are in place to prevent the misuse of research studies for promotional purposes and to maintain the integrity and scientific rigor of non-interventional research. The primary focus should be on generating reliable evidence, improving patient care, and advancing scientific knowledge in an unbiased and ethical manner.

Share this story...

Real World Evidence (RWE) 101 – Why Should Non-Interventional Studies NOT be Promotional?2023-08-07T14:15:07+00:00

Real World Evidence (RWE) 101 – The Common Rule

RWE 101 – The Common Rule

The Common Rule plays a significant role in the governance of observational studies. The Common Rule refers to a set of regulations and ethical principles designed to protect human subjects participating in research studies conducted or supported by federal agencies in the United States. It sets the standards for the ethical conduct of research and ensures the protection of individuals involved in research studies.

Observational studies, which are a type of study design used in RWE research, involve the collection and analysis of data from participants in their real-world settings. These studies aim to assess outcomes and associations between various factors, such as treatments, interventions, or exposure to certain conditions, without any intervention or manipulation by the researcher.

The Common Rule establishes the following key principles and requirements:

Informed Consent: The Common Rule emphasizes the importance of obtaining informed consent from individuals participating in research studies. Researchers must provide participants with clear and understandable information about the study, its purpose, risks, potential benefits, and any other relevant details. Informed consent ensures that participants have the necessary information to make an informed decision about their participation.

Institutional Review Board (IRB) Oversight: The Common Rule requires that all research involving human subjects undergo review by an IRB. The IRB evaluates the study’s ethical implications, safeguards the rights and welfare of participants, and ensures that the research adheres to the Common Rule’s principles. IRBs play a critical role in assessing the risks and benefits of observational studies and determining whether they meet ethical standards.

Privacy and Confidentiality: Observational studies often involve the collection of sensitive data from participants, such as medical records or personal information. The Common Rule mandates that researchers take appropriate measures to protect the privacy and confidentiality of individuals involved in the study. This includes implementing safeguards to prevent unauthorized access, use, or disclosure of participant data.

Balancing Risks and Benefits: The Common Rule requires researchers to conduct a thorough risk-benefit analysis of the observational study. They must assess the potential risks associated with data collection and analysis and weigh them against the potential benefits of the research. This analysis helps ensure that the benefits of the study justify any potential risks to the participants.

By adhering to the Common Rule, researchers can ensure that observational studies in RWE are conducted ethically, with proper safeguards for participant rights, welfare, and privacy. The Common Rule helps maintain the integrity of research and promotes public trust in the scientific community’s ability to generate reliable and valuable real-world evidence.

Share this story...

Real World Evidence (RWE) 101 – The Common Rule2023-08-07T13:58:31+00:00

USA | Draft FDA Guidance: Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products 

Please login to view this page.

USA | Draft FDA Guidance: Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products 2022-08-07T16:57:47+00:00

Insights – Document Management and Archiving Requirements for Observational Studies


The TMF Reference Model’s specially designed Study Master File will not have an impact on the regulatory requirements for conducting real world research studies in the country of interest…but if used…it will make your real world research studies much easier to manage and less resource intensive (and less frustrating!).

5 NOVEMBER 2021 – Did you know that there is a DIA TMF Reference model for observational studies? 

  • [Lean Version] Real-World Studies Document Index Provides a proposed Document Index for use on real-world studies, based on the TMF Reference Model for clinical trials (v1.0 Approved 29-July-2020) [1]
  • [Detailed Version – with guidance notes] Study Master File [2]

For years, those of us who have been running observational studies (also known as non-interventional studies) have been the ‘poor relation’ with regards to document management tools and offerings.  We’ve had to ‘bootstrap’ existing clinical trial tools to fit the significantly different document requirements for observational studies.  This is why, in 2018 a group of frustrated experts got together with the blessing of the TMF Reference Model Steering Committee…and the rest, as they say…is history…

Why is a Stand Alone Study Master File Needed?

Those of you who are involved in Real World Studies (RWS) know that trying to file your documents using the existing TMF Reference Model (TMF RM) based on ICH E6 can be challenging.  Your study isn’t a clinical trial and as a result, at least 40% of the artifacts in the index are irrelevant.  The result?  You start from the beginning every time you set up a new study and  ‘switch off’ the tabs that aren’t applicable. Alternatively, you may be required to use the existing TMF RM in accordance with your organisation’s policy and disregard tabs that aren’t relevant. Additionally, you hope that an auditor of your ‘real world study TMF’ understands your study and doesn’t penalize you for missing documents (or documents that were never generated, because your study is not a clinical trial).

Real World Studies are increasingly being used to support drug development, product licensing, label claims and reimbursement. Consequently the need for an audit-ready framework has become a critical requirement to effectively collect and manage the documents that evidence integrity in relation to study conduct and study data.

Designing a Solution

To address this, a working group of RWS experts* convened in March 2018 to develop a framework for filing essential documents for non-interventional and observational studies. In designing the Real World Study-Document Index (RWS-DI), the group took into account the ethical standards, regulatory requirements, guidelines and industry best practices applicable to non-interventional studies (NIS). The group developed the RWS-DI based on a prospective study design to provide maximum coverage of the potential documents (or artifacts) across the range of real world study designs, from non-interventional studies, retrospective chart reviews, to prospective product registry studies.

The result is a listing of core and recommended artifacts relevant to Real World Studies (which are not clinical trials) while remaining  as consistent as possible with the TMF-RM format and structure. The RWS-DI adapted the TMF RM removing artifacts specific to clinical trials such as Investigational Product Dossier (IMPD) or Investigator’s Brochure (IB) and replaced terminology such as ‘trial’ with ‘study’ and ‘subject’ with ‘patient’.

The RWS-DI was sanctioned under the auspices of the DIA TMF Reference Model Steering Committee throughout its development. It was endorsed by the DIA TMF Reference Model Steering Committee as a ‘stand-alone’ deliverable for launch to the wider research community. It is anticipated that, as the RWS-DI becomes widely adopted, it will evolve to reflect user community requirements. Feedback, enquiries, and suggestions for enhancements for incorporation in future versions can be made using the e-mail address

The Real World Studies Working Group comprised of the following members, all of whom work within the Real-World Study environment and contributed their expertise throughout the duration of the project.

Shelley Brigstock Study Project Manager, Novo Nordisk

Kath Firth Head of Quality Operations, GSK

Tara Isherwood               Senior Director, Regulatory Advice and Delivery, Syneos Health

Russell Joyce Director and Principal Consultant, Heath Barrowcliff Consulting

Jeff Kirsch* Senior Director, Quality & Risk Management and Governance, GSK

Stuart McCully               Founder, Phoenix RWR

Linda Rudolph               Principal Consultant, Quality Werx, LLC


*Currently-Director and Founder, Jeff Kirsch Consulting, Ltd

Want to Learn More?

Speak to the Master Architect – Russell Joyce.  Russell is one of the founders of the TMF Reference Model and the chair of the Study Master File working group (Real World Study Document Index)





1. Real-World Studies Document Index Provides a proposed Document Index for use on real-world studies, based on the TMF Reference Model for clinical trials (v1.0 Approved 29-July-2020)


2. Study Master File


Insights – Document Management and Archiving Requirements for Observational Studies2022-08-07T17:06:27+00:00
Go to Top