Ideally, we would classify studies according to the level of intervention i.e., interventional, low intervention, and non-interventional.

However, although we assume clinical trials are the opposite of non-interventional studies and are therefore ‘interventional’, most regulators have been hesitant to define ‘intervention’ in their regulations.

In Europe, the EU Clinical Trials Regulation [ref 1], defines ‘clinical trials’, ‘low interventional clinical trials’, and ‘non-interventional studies’.

By definition [ref 1], a clinical trial is an investigation in humans that involves a medicinal product and the assignment of the patient to a therapeutic strategy is decided in advance  by the trial protocol i.e., protocol-defined healthcare intervention.

In a low intervention clinical trial (LICT), the assignment of the patient to a therapeutic strategy is still decided in advance  by the trial protocol, but the medicinal product is approved and used as per marketing authorisation.  So once again there is a protocol-defined healthcare intervention. In the case of a LICT, there are additional patient safety considerations i.e., any additional diagnostic or monitoring procedures that are implemented as part of the LICT must pose no more than minimal additional risk or burden to the safety of the trial participants compared to normal clinical practice.  Why?  If you increase the degree of risk to the patient above normal clinical practice…you have exceeded the ‘low risk’ threshold and the trial reverts to a ‘normal’ clinical trial.

Another consideration for LICT is that there is allowance for using medicinal products off-label (e.g., paediatric or oncology drugs), but their use in this context must be supported by “published scientific evidence on the safety and efficacy of those investigational medicinal products”…and again…the trial must meet the ‘low risk’ requirements such that any additional diagnostic or monitoring procedures applied to the patient poses no more than minimal additional risk or burden to the safety of the trial participants compared to normal clinical practice. 

Put simply, clinical trials and low intervention clinical trials involve protocol-defined healthcare interventions.

What about non-interventional studies?

By definition [ref 1], a non-interventional study is an investigation in humans that involves a medicinal product and the assignment of the patient to a therapeutic strategy is NOT decided in advance  by the trial protocol i.e., there is NO protocol-defined healthcare intervention. This means there are NO protocol-specified activities or procedures that alter the patients’ treatment regimens or plans i.e., there are no additional diagnostic or monitoring procedures applied to the patient that impact the patients’ treatment.

In summary, in Europe both low intervention clinical trials (LICT) and non-interventional studies (NIS) are investigations in humans that involves a medicinal product.  LICT involve protocol-defined healthcare interventions, whereas NIS do not.

References:

[1] EU Clinical Trials Regulation (Regulation EU/536/2014): https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02014R0536-20221205

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.