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#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?

#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?

 

It’s a simple question. Actually…no it isn’t.

The EU defines a non-interventional study as a “clinical study other than a clinical  trial” 😳 [ref 1].  Whereas the US FDA talks about “non-interventional (observational) studies”[ref 2].

So…let’s simplify things…for the sake of your sanity and mine.

In Europe, by definition [ref 1], a non-interventional study must involve a drug.  If your clinical study does not involve a drug…then by regulatory definition it cannot be a non-interventional study. Meaning?  Any other type of study with a non-interventional design will be an observational study…which may or may not be defined at the local level.

The EMA list of metadata for the Real World Data catalogues (which go live in February 2024) [ref 3] define the drug study types as ‘clinical trial’ or ‘non-interventional study’.  The non-interventional study, study designs are defined as: cohort| case-control| case-only| cross-sectional| ecological| cluster design| systematic review and meta-analysis.  Note the absence of ‘observational’.

In the USA, the terms ‘non-interventional study’ and observational study are used interchangeably:

A non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol (as per Section II of the FDA Guidance) [ref 2].

However, the FDA definition implies that a non-interventional study must involve a drug.

In summary, in both Europe and America, a non-interventional study must involve a drug.  If your clinical study does not involve a (marketed) drug…then by regulatory definition it cannot be a non-interventional study.

 

References:

[1] Article 2.2(4) of Regulation EU/536/2014: https://eur-lex.europa.eu/eli/reg/2014/536

[2] Section II of the FDA Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (August 2023): https://www.fda.gov/media/171667/download

[3] Section 2.2(II) of the EMA List of Metadata for Real World Data Catalogues (May 2022): https://www.ema.europa.eu/en/documents/other/list-metadata-real-world-data-catalogues_en.pdf

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?2024-02-01T14:38:55+00:00

Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study – Supplement

RWE 101 – The Tuskegee Syphilis Study – Supplement

 

The Tuskegee Syphilis Study, conducted between 1932 and 1972 by the United States Public Health Service (USPHS), stands as one of the most infamous and ethically questionable experiments in the history of human research. The study intended to observe the natural history of untreated syphilis. Researchers did not collect informed consent from participants. Researchers did not offer treatment, even after it was widely available. The study was terminated after 40 years following publication of news articles about the study.

“The government induced these men to participate in a study in which the government represented that the participants were being treated for whatever their ailments were…They were never told what their ailment was…They never gave their consent to be involved in a study…Nor did they realise they were part of a study until the story broke in July 1972…Treatment was knowingly withheld for 40 years” – Fred D Gray – Attorney, 8th April 1997

Its repercussions have had far-reaching effects on the regulation of observational studies, medical ethics, and trust in healthcare institutions, especially among minority communities.

  1. Introduction of Ethical Guidelines: The Tuskegee study helped accelerate the development of ethical standards for observational studies, notably the Belmont Report in 1979. The report outlined three basic principles: respect for persons, beneficence, and justice. It prescribed informed consent, an understanding of potential risks and benefits, and the equitable selection of research subjects. These principles, born out of a response to the unethical practices in Tuskegee and other studies, have become the bedrock of research ethics.
  2. Introduction of Regulations: In 1974 the National Research Act was signed into law and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed. In 1991 the Federal Policy for the Protection of Human Subjects (‘Common Rule’) (45 CFR 46) was implemented.
  3. Informed Consent: One of the main lessons from the Tuskegee study was the importance of informed consent. In the study, participants were not told they had syphilis, nor were they informed about the nature of the experiment. As a result of public outcry, it is now mandatory for researchers to provide potential participants with comprehensive information about the study and its potential risks and benefits.
  4. Protection for Vulnerable Populations: The Tuskegee study highlighted the need for special protections for vulnerable populations in observational studies. The mostly poor, uneducated African American men involved were exploited due to their socioeconomic status and lack of access to quality healthcare. The fallout from Tuskegee led to additional safeguards for marginalized populations to prevent similar abuses.
  5. Institutional Review Boards (IRBs): After the Tuskegee study, the requirement for Institutional Review Boards became more widespread. IRBs are responsible for reviewing and monitoring research involving humans to ensure ethical standards are met. Their role is to protect the rights and welfare of the research subjects.
  6. Transparency and Accountability: The Tuskegee Syphilis Study was marked by a lack of transparency and accountability. The study was conducted without adequate oversight or scrutiny. This led to the development of regulations requiring transparency in the conduct of studies, data sharing, and mechanisms for accountability in the case of ethical breaches.
  7. Public Trust and Participation: The Tuskegee study severely damaged public trust, particularly among African Americans, in medical research and healthcare institutions. This has implications for the regulation of observational studies, as it underscores the importance of building and maintaining public trust for successful research participation.
  8. Cultural Competency: The racial implications of the Tuskegee study brought to light the importance of cultural competency in research. Researchers are now required to respect the cultural norms and values of the populations they study, and training in cultural competency has become a norm in many research settings.
  9. Training in Research Ethics: Following the Tuskegee study, training in research ethics became a requirement for investigators conducting human subject research. This training typically includes a discussion of the Tuskegee study as an example of what not to do.
  10. International Impact: The Tuskegee study had a global impact on observational study regulation. The Declaration of Helsinki, a set of ethical principles regarding human experimentation, was updated in response to the ethical violations in Tuskegee and similar studies.

“Medical professionals willingly and intentionally let human beings suffer from a treatable, and then later a curable illness. These researchers knew that mercury and arsenic compounds could treat the disease, but the Tuskegee men did not receive the medicine. Later the researchers knew that penicillin could cure the disease, but again, the Tuskegee men did not get the medicine. They didn’t get treated until the 40 year study was discovered and stopped amid public outcry in 1972. It was a disgraceful episode for American Scientists” – Vice President Al Gore, 16th May 1997 [See also…Presidential Apology]

In conclusion, the Tuskegee Syphilis Study has had a profound impact on the regulation of observational studies in the USA.

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Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study – Supplement2023-08-07T13:51:32+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

RWE 101 – Do I Need IRB Approval for My Observational Study?

RWE 101 – Do I Need IRB Approval for My Observational Study?

In general, observational studies that involve human subjects require Institutional Review Board (IRB) approval to ensure that the study is conducted in an ethical manner and that the rights and welfare of study participants are protected. This applies to both clinical trials and observational studies, including those using real-world evidence (RWE).

IRB approval is required because observational studies may involve the collection of personal or sensitive information from study participants, or the implementation of interventions or procedures that may pose risks to participants. IRBs review study protocols to ensure that the study design is scientifically sound, that the risks to participants are minimized, and that the potential benefits of the study outweigh any potential harms.

However, there are some exceptions to this requirement for IRB approval. For example, if the RWE study uses de-identified data and does not involve any interventions or interactions with human subjects, IRB approval may not be required. Additionally, certain types of RWE studies may be exempt from IRB review under certain circumstances, such as studies that use existing data and do not involve the collection of new data from human subjects.

It is important to note that the specific requirements for IRB approval may vary by country or region, and by the specific study design and research question. Therefore, it is important to consult with local regulations and guidelines, as well as with an IRB or ethics committee, to determine whether IRB approval is required for a specific observational study using RWE.

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RWE 101 – Do I Need IRB Approval for My Observational Study?2023-08-07T22:42:37+00:00
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