Interventional vs Non-Interventional – Common Misunderstanding and Simple Solutions

Words are Powerful!

Something as simple as a single word can de-rail your study, sending you down a path you didn’t anticipate…adding time, cost, frustration and stress…that word?…

INTERVENTION

Spider-Man-Quote

Common Sense Tells us that a Blood Draw is ‘Interventional’ and if it’s ‘Interventional’ our Study Must be a Clinical Trial

We assume that clinical trials are interventional and therefore anything that is interventional is a clinical trial. It’s a logical assumption, but…it doesn’t align with the definition of a clinical trial [1] and therefore (and more importantly for us) what isn’t a clinical trial. Although TREATMENT INTERVENTION is the fundamental core principle of clinical trials, “treatment intervention” is never fully or spefically defined in clinical trials legislation (exception is France [2]). Legislation defines non-intervention [3] and low intervention [4], but not intervention. Don’t get me wrong, references are made to “intervention” and “interventional” [5], but in the absence of clear regulatory definitions, this just adds to the confusion.

Point in case…if we apply logic and common sense to the meaning of a ‘non-interventional study’ we would assume that it doesn’t include interventions. Actually, from a regulatory perspective, a non-interventional study is a study where physical interventions are allowed (usually and within reason)[6]. So, non-interventional studies are not actually ‘non-interventional’ in the context of ‘physical interventions’.  BRAIN FRY!

Let’s look at some examples of common ‘interventions’ found in real world research:

  • PHYSICAL INTERVENTION – You want to include collection of biosamples (5ml blood draw) to support a research hypothesis knowing that the biosampling will not impact the normal care of the patient

  • DIGITAL INTERVENTION – You want to study the impact of a disease education app on patient quality of life

  • PSYCHOLOGICAL INTERVENTION – You want patients to fill out detailed and lengthy questionnaires (e.g., PROs) to help you understand the real-world effectiveness of the routine treatment they are already receiving

  • NO INTERVENTION – You want to collect effectiveness information on the patients’ normal care (treatment) to provide a credible/ robust baseline for future gene therapy

The concern is that these ‘interventions’ shift the proposed research from ‘non-interventional’ to ‘interventional’ and therefore make them clinical trials.  The impact being significant increases in time and cost…cue ‘challenging’ stakeholder meetings.

The Solution?  Refreshingly Simple!

Make no subjective assumptions. Go back to the scientifc concept of first principles. Is the proposed reesearch a clinical trial based on the applicable regulatory definitions (see below)? If not, what is it? Again, base the ‘discovery process’ on the applicable regulatory definitions.

Subjectivity and ‘histrionics’ (this is what we’ve always done) will only lead to confusion and unecessary stress. Keep your discovery process simple and clean…”this study is a non-interventional study because”…

References

[1] Clinical Trial = Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy (as per Article 2(a) of Directive 2001/20/EC).

[2] Treatment Intervention: France – Law n ° 2012-300 of March 5, 2012 relating to research involving the human person (known as the Jardé law), as amended by ordinance n ° 2016-800 of June 16, 2016, distinguishes 3 categories of research: The research mentioned in 1 ° of Article L. 1121-1 of the Public Health Code: This is the research that involves an intervention on people who are not without risk for them. This research includes research on drugs, on other health products (mentioned in Article L. 5311-1), and also on research not relating to health products (for example research on food). They correspond to what was previously defined as “biomedical research”. They can only be implemented after authorization from the ANSM and a favorable opinion from a CPP (article L. 1121-1 of the CSP).

[3] Non-Interventional Trial = A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data (as per Article 2(c) of Directive 2001/20/EC).

[4] Low Intervention Clinical Trial = Means a clinical trial which fulfils all of the following conditions: (a) the investigational medicinal products, excluding placebos, are authorised; (b) according to the protocol of the clinical trial, (i) the investigational medicinal products are used in accordance with the terms of the marketing authorisa­tion; or (ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and (c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned (as per Article 2.2(3) of Regulation EU/536/2014)

[5] Overview of Legislation Refering to ‘Intervention’ and ‘Non-Intervention’ (Download)