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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.

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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 – Seeding Studies

RWE 101 – Seeding Studies

Seeding studies, in the context of real-world evidence (RWE), refer to studies that were conducted by pharmaceutical or medical device companies after a product’s approval or market introduction. These studies aimed to promote/ increase the market presence of the approved drug. Regulators like the FDA and EMA view seeding studies as unethical for several reasons.

Link: https://lnkd.in/e9vP4KxA

1.  Misleading intent: Seeding studies were primarily conducted to influence prescribing habits, promote a specific product, and create a favourable impression among healthcare providers. This promotional intent conflicts with the primary objective of research, which should be to generate unbiased and reliable evidence.

2.  Methodological flaws: Seeding studies often lacked rigorous scientific methodology. Some were observational in nature and lacked control groups or blinding, making it difficult to draw valid conclusions about product safety and efficacy. The data collected was of poor quality, limiting its utility for meaningful analysis and decision-making.

3. Transparency and bias: Seeding studies were sponsored by the manufacturers of the products being studied. This created potential conflicts of interest and raised concerns about transparency and data integrity. The financial relationships between study sponsors and participating healthcare professionals potentially biased the study results and compromised the independence and objectivity of the research.

4. Publication bias: Seeding studies were susceptible to publication bias, where positive or favourable results were more likely to be published, while negative or unfavourable findings were suppressed or unreported. This selective reporting distorted the overall evidence base and misled healthcare providers and regulators in their decision-making.

5. Ethical considerations: Seeding studies raised ethical concerns regarding patient safety and informed consent. Participants were not adequately informed about the purpose, risks, and benefits of these studies.

Regulatory bodies, including the FDA and EMA, strive to protect patient welfare and ensure the integrity of the research process. They require studies to be conducted with scientific rigor, unbiased intent, and adherence to ethical principles. In the EU, it is a legal requirement that non-interventional studies are not promotional (Article 107m(3) of Directive 2001/83/EC).

It is important for researchers, industry sponsors, and regulators to maintain transparency, adhere to ethical guidelines, and prioritize patient welfare in the pursuit of real-world evidence. By doing so, the integrity of RWE can be preserved, and reliable evidence can guide healthcare decisions and promote the well-being of patients.

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Real World Evidence (RWE) 101 – Seeding Studies2023-08-07T14:09:15+00:00

Real World Evidence (RWE) 101 – HIPAA

RWE 101 – HIPAA

HIPAA (Health Insurance Portability and Accountability Act), enacted in 1996, is a federal law in the United States that establishes regulations for the protection of individuals’ health information and safeguards their privacy and confidentiality.

In the context of RWE, HIPAA applies to the collection, use, and disclosure of protected health information (PHI) obtained from patients’ medical records, claims data, or other sources. Here’s an overview of HIPAA’s impact on RWE:

Privacy Rule: The HIPAA Privacy Rule sets standards for the protection of individuals’ PHI. It outlines the permissible uses and disclosures of PHI by covered entities, such as healthcare providers, health plans, and healthcare clearinghouses. Researchers utilizing RWE must adhere to these privacy regulations when accessing and handling PHI.

De-identification: HIPAA provides guidelines for de-identifying PHI, allowing researchers to use data without requiring patient consent.

De-identified data is stripped of direct identifiers (e.g., names, addresses) and must have a low risk of re-identification. Researchers utilizing de-identified data are exempt from certain HIPAA requirements but must still handle data responsibly and protect against re-identification risks.

Limited Data Set: HIPAA allows the use and disclosure of a limited data set without patient authorization. A limited data set contains PHI with certain direct identifiers removed, but it may still include information such as dates and geographic data. Researchers must enter into a data use agreement with the covered entity providing the limited data set, ensuring compliance with HIPAA regulations.

Research Authorization: In some cases, researchers may seek individual authorization from patients to access their PHI for RWE studies. HIPAA specifies the required elements for a valid authorization, including a clear description of the information to be disclosed, the purpose of the disclosure, and the rights of the individual regarding their PHI.

Security Rule: The HIPAA Security Rule mandates safeguards to protect the confidentiality, integrity, and availability of electronic PHI (ePHI). It requires covered entities and their business associates to implement administrative, physical, and technical safeguards to secure ePHI against unauthorized access, use, or disclosure.

Penalties and Enforcement: HIPAA violations can lead to severe penalties, including civil and criminal sanctions.

In summary, HIPAA plays a critical role in protecting individuals’ health information in the context of RWE. Researchers must understand and adhere to HIPAA regulations when handling PHI, ensuring privacy and confidentiality while conducting valuable RWE studies. Compliance with HIPAA requirements safeguards patient rights, fosters trust, and promotes the responsible use of health data for research purposes.

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Real World Evidence (RWE) 101 – HIPAA2023-08-07T14:04:10+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.

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

Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)

RWE 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)

The Tuskegee Syphilis Study, conducted from 1932 to 1972, stands as a notorious example of unethical human research. Its fallout had substantial implications on the regulation of observational studies:

Ethical Guidelines: The Tuskegee study expedited the development of ethical standards, including the Belmont Report (1979). The report emphasized respect for persons, beneficence (acting in a way that brings about positive outcomes and promotes the welfare of others), and justice (the principle of treating people fairly and equitably), all crucial in research ethics.

Informed Consent: The Tuskegee study underscored the importance of informed consent. It is now required for researchers to provide comprehensive information about the study and its potential risks and benefits.

Protection for Vulnerable Populations: The study highlighted the need for protections for vulnerable populations. Additional safeguards have since been implemented to prevent similar abuses.

Institutional Review Boards (IRBs): Post-Tuskegee, the requirement for IRBs became more prevalent. IRBs review and monitor research involving humans to ensure ethical standards.

Transparency and Accountability: The study led to regulations mandating transparency, data sharing, and mechanisms for accountability in the case of ethical breaches.

Public Trust and Participation: The Tuskegee study damaged public trust, particularly among African Americans. This underlines the importance of building and maintaining public trust for research participation.

Cultural Competency: The racial implications of the Tuskegee study highlighted the importance of cultural competency in research. Training in cultural competency has since become a norm.

Training in Research Ethics: The study led to mandatory training in research ethics for investigators conducting human subject research.

International Impact: The study had a global impact on observational study regulation. It influenced updates to the Declaration of Helsinki, an international set of ethical principles regarding human experimentation.

For more details about the Tuskegee Syphilis Study see the RWE 101 Supplement I published today…

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Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)2023-08-07T13:45:24+00:00

Real World Evidence (RWE) 101 – Observational Study vs Non-Interventional Study

RWE 101 – Observational Study vs Non-Interventional Study

In the context of real-world evidence (RWE), the terms “observational study” and “non-interventional study” are often used interchangeably to refer to studies that collect data outside the controlled environment of a clinical trial. However, it’s worth noting that some subtle differences can exist based on the specific context or regulatory guidelines. Here’s an overview:

[1] Observational Study: An observational study is a research design where researchers observe and collect data on participants without intervening or administering any specific treatment. Observational studies aim to analyze associations, correlations, or patterns in real-world settings. They can be prospective (following participants over time) or retrospective (analyzing existing data or medical records).

[2] Non-interventional Study: A non-interventional study is a study type (EU and US regulatory definition)  that does not involve any healthcare or treatment interventions imposed by researchers. It is often used as an umbrella term for studies that collect data in real-world settings, without manipulating variables. Non-interventional studies are primarily focused on describing, analyzing, or assessing outcomes, exposure, or associations.

It’s important to note that regulatory guidelines and definitions may vary across different regions and agencies. For instance, the US FDA’s guidance on RWE refers to “real-world studies”, “observational Studies”, and “non-interventional (observational) studies”, while the European Union Clinical Trials Regulation (Regulation EU/536/2014) uses the term “non-interventional studies.” However, in practice, the intent of these studies—collecting data without actively intervening—is often similar.

In the context of RWE, both observational studies and non-interventional studies typically leverage real-world data sources such as electronic health records, claims databases, registries, surveys, or patient-reported outcomes. They aim to generate evidence (real world evidence) on treatment outcomes, comparative effectiveness, safety profiles, and other healthcare-related factors.

Ultimately, the precise terminology used may vary, but the fundamental principle is that observational studies and non-interventional studies within the context of RWE both involve the collection and analysis of real-world data without actively imposing healthcare or treatment interventions on participants.

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Real World Evidence (RWE) 101 – Observational Study vs Non-Interventional Study2023-08-07T13:29:05+00:00

Real World Evidence (RWE) 101 – Are Non-Interventional Studies Regulated?

RWE 101 – Are Non-Interventional Studies Regulated?

Yes, non-interventional studies (NIS) are regulated. While the specific regulations and requirements may vary by country, there are generally guidelines and provisions in place to ensure the conduct and reporting of non-interventional studies meet certain standards.

Here are some key points related to the regulation of non-interventional studies:

Ethical Considerations: Non-interventional studies involving human participants must adhere to ethical principles and guidelines (i.e., Declaration of Helsinki) and be approved by an ethics committe (IRB/REC). These guidelines often cover aspects such as informed consent, confidentiality, privacy protection, and the rights and welfare of study participants.

Data Protection: Regulations related to data protection and privacy, such as the EU General Data Protection Regulation (GDPR), are applicable to non-interventional studies. Researchers must ensure that the collection, storage, and processing of personal data comply with these regulations.

Regulatory Oversight: Regulatory authorities may have oversight over non-interventional studies, particularly when the studies are the results of a regulatory commitment (e.g., PMRs and PASS). In the EU, for example, the EMA provides guidance on non-interventional post-authorisation safety studies (PASS) (GVP Module VIII).

Good Pharmacovigilance Practices (EU): Non-interventional studies focused on post-authorization safety assessments of medicinal products are subject to good pharmacovigilance practices. These practices include the collection, analysis, and reporting of adverse drug reactions and safety data.

Reporting Requirements: Non-interventional studies may have reporting requirements (e.g., EU PAS Register) to ensure transparency and accountability. This may include the submission of study protocols, study results, safety updates, or other relevant data to regulatory authorities or ethics committees.

It’s important to note that the specific regulations and requirements for non-interventional studies can vary between countries and regions. Researchers conducting non-interventional studies should be familiar with the applicable regulations in their jurisdiction and seek guidance from regulatory authorities, ethics committees, or relevant professional organizations to ensure compliance with the required standards.

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Real World Evidence (RWE) 101 – Are Non-Interventional Studies Regulated?2023-08-07T13:12:49+00:00

Real World Evidence (RWE) 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)

RWE 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)

 

In the context of real-world evidence (RWE) and regulatory frameworks, postmarket requirements (PMRs) and post-authorization safety studies (PASS) are two distinct concepts that focus on monitoring and assessing the safety and effectiveness of medical products after they have been approved or authorized for use. Here’s an explanation of each:
 
Postmarket Requirements (USA): Postmarket requirements refer to the obligations imposed by the US FDA on manufacturers or sponsors of medical products (such as drugs and biologics) after they have been approved for marketing. These requirements are intended to gather additional data and monitor the product’s safety and effectiveness in real-world settings and INCLUDE observational studies that sponsors are required to conduct.
 
Compliance with these requirements ensures ongoing evaluation and surveillance of the product’s safety and effectiveness throughout its lifecycle.
 
Post-Authorization Safety Studies (EU): Post-authorization safety studies (PASS) are specific studies conducted to further assess the safety profile of a medical product in real-world settings after it has been authorized for use. PASS is a type of post-marketing study designed to gather additional safety data that may not have been captured during pre-market clinical trials due to the limited sample size, restricted patient population, or duration of the trials.
 
Key aspects of post-authorization safety studies include:

Study design: PASS typically involves observational study designs, such as cohort studies or case-control studies, to evaluate the safety outcomes associated with the product’s use in a larger patient population.

Sample size: PASS often involves a larger number of participants than pre-market clinical trials to increase the likelihood of detecting rare or long-term safety events.

Data collection: Data for non-interventional PASS is collected from real-world sources, such as electronic health records, claims databases, registries, or other healthcare databases.

Safety outcomes: The primary focus of PASS is to assess and monitor the occurrence of safety events, adverse drug reactions, or any potential safety concerns associated with the product’s use.
 
Post-authorization safety studies are typically conducted as a regulatory requirement, based on the authorization conditions set by the EMA (i.e., Category 1 and 2 PASS). The findings from these studies contribute to ongoing risk-benefit assessments of the product and inform regulatory decision-making, labelling updates, or risk management strategies.
 
Overall, postmarket requirements encompass a broader set of obligations imposed on manufacturers after a product’s approval, while post-authorization safety studies specifically focus on conducting additional studies to assess the safety profile of authorized medical products in real-world settings.

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Real World Evidence (RWE) 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)2023-08-07T13:02:45+00:00

Real World Evidence (RWE) 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study

RWE 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study

Interventional Clinical Trial: In this type of study, researchers actively intervene by assigning participants to different groups, administering specific treatments, or manipulating variables. The primary objective is to assess the safety and efficacy of new interventions e.g., drug or medical device.
 
Key characteristics of interventional clinical trials include:
 
Randomization: Participants are randomly assigned to different groups, such as the experimental group receiving the intervention and the control group receiving a placebo or standard treatment.

Intervention: Researchers actively administer a specific treatment or intervention to the participants.

Control Group: There is often a control group that receives a placebo or standard treatment for comparison.

Primary Outcomes: Trials are designed to measure predefined primary outcomes, such as improvements in health outcomes, survival rates, or reduction in symptoms.

Regulatory Oversight: Interventional trials require regulatory approval and are usually subject to stricter (risk-proportionate) regulations than non-interventional studies.
 
Non-interventional Study: These studies focus on collecting data without any active healthcare or treatment intervention imposed by the researchers. Researchers observe and collect information from participants in their natural settings (real world settings) or through retrospective analysis of existing data (secondary use of existing data).
 
Key characteristics of non-interventional studies include:
 
Observation: Researchers observe participants and collect data without actively intervening in the healthcare management of the participant or administering any specific treatment (treatment intervention).

Natural Setting: Data is collected in the real-world clinical practice or from existing databases, medical records, surveys, or interviews.

Descriptive Analysis: Non-interventional studies often aim to describe and analyze associations, relationships, patterns, or risk factors in the population under study.

Retrospective or Prospective: Data can be collected retrospectively by analyzing past records or prospectively by following participants over time.

No Randomization: Participants are not randomly assigned to groups, and treatment decisions are made by healthcare providers according to routine clinical practice.

Regulatory Oversight: Every country regulates non-interventional studies differently. The regulatory burden can therefore be much higher than expected.
 
Both ‘interventional’ clinical trials and non-interventional studies play important roles in advancing medical knowledge. Interventional trials provide more rigorous evidence for evaluating new interventions, while non-interventional studies offer insights into real-world effectiveness, population health, and long-term outcomes.

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Real World Evidence (RWE) 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study2023-08-07T12:55:06+00:00

Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

RWE 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

No, “clinical study” and “clinical trial” are not necessarily synonymous in the context of non-interventional studies in the EU.

In general, a clinical study refers to any investigation involving human participants that is intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products, or to identify any adverse reactions to one or more medicinal products. This can include both (interventional) clinical trials and non-interventional studies.

A clinical trial, on the other hand, specifically refers to a type of interventional clinical study where one or more medicinal products are tested in human participants with the aim of evaluating their safety and/or efficacy i.e., there is a treatment intervention involving a medicinal product.

Non-interventional studies (NIS) are observational studies that do not involve any treatment interventions or protocol-dictated administration of a medicinal product. They are designed to observe patients in their natural clinical setting and collect data on the outcomes of a specific drug or treatment intervention.

So, while a clinical trial is a type of clinical study, not all clinical studies are clinical trials.
 
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 includes a new definition of ‘clinical trial’ provided in the Glossary, which 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.

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Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?2023-08-07T12:48:43+00:00
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