Following on from my last blog post about the new Clinical Trials (CT) Regulation EU No. 536/2014, I’d like to have a look at a few terminology changes and some new definitions that will come in with the new legislation.
Clinical study and clinical trial: no longer synonyms
In the 2015 version of the ICH GCP Guideline, clinical study and clinical trial are classified as synonyms. This shared definition was also used for clinical trial in the old Clinical Trials Directive 2001/20/EC :
“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
However, in the new Clinical Trials Regulation, this definition applies to clinical study and refers to all medicinal products, not just investigational medicinal products:
‘Clinical study’ means any investigation in relation to humans intended: (a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products; (b) to identify any adverse reactions to one or more medicinal products; or (c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products; with the objective of ascertaining the safety and/or efficacy of those medicinal products;
Clinical trial is now understood as a type of clinical study that uses medicinal products outside normal clinical practice, i.e. it involves some level of intervention:
‘Clinical trial’ means a clinical study which fulfils any of the following conditions: (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned; (b) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
In short, clinical studies are now subdivided into clinical trials and non-interventional studies.
- Spanish: In the new legislation, clinical study and clinical trial are still translated as estudio clínico and ensayo clínico.
Non-interventional trial: now non-interventional study
This is a logical change. Now that clinical trials are interventional by definition, non-interventional trial is a contradiction in terms, which is why it has been changed to non-interventional study.
- Spanish: Note that in the old CT Directive, non-interventional trial was translated as ensayo no intervencional, but in the new CT Regulation, non-interventional study is estudio observacional.
Low-intervention clinical trial: new term
As mentioned in my previous blog post, this is a new clinical trial category that defines trials with only a minimal additional risk to subject safety compared to normal clinical practice. A low-intervention clinical trial therefore has less stringent rules for monitoring, master file contents and IMP traceability.
- Spanish: ensayo clínico de bajo nivel de intervención
Auxiliary medicinal product: new term
According to the new CT Regulation:
‘Auxiliary medicinal product’ means a medicinal product used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product;
This term was not defined at all in the old CT Directive. However, the concept isn’t new, because it refers to all non-investigational medicinal products used in clinical trials, such as rescue medication and challenge agents. Note that concomitant medication is not included in this definition.
- Spanish: medicamento auxiliar
Substantial amendment/substantial modification: the same or different?
On the surface, the term modification appears to have replaced amendment in the new Regulation. Substantial modification even has a specific definition now:
‘Substantial modification’ means any change to any aspect of the clinical trial […] which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial;
However, the dictionary definition of amendment actually refers to a change in a written text (e.g., the protocol or informed consent), whereas modification refers here to a change in the clinical trial itself and the new procedure for authorising such modifications. For example, the addition of a new site, a change in site suitability and a change of principal investigator are all considered to be substantial modifications.
Therefore, we should add substantial modification to our glossaries, but not necessarily replace amendment, which will still be found with reference to protocols and informed consents.
- Spanish: modification is translated as modificación in the new legislation. Where amendment is used in clinical trial documentation (for procedures not classified as a substantial modification), the Spanish enmienda is still used.
- Substantial is now translated as sustancial, whereas before it was relevante.
Temporary halt: new term
A temporary halt refers to a suspension of a clinical trial triggered by the sponsor, whereas a suspension is initiated by a Member State.
- Spanish: paralización temporal
Legal representative: now legally designated representative
The addition of designated to this term brings the EU legislation more into line with the ICH GCP guideline definition of legally acceptable representative. In practice, the meaning depends on the law of each Member State:
‘Legally designated representative’ means a natural or legal person, authority or body which, according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject who is an incapacitated subject or a minor;
- Spanish: The translation has similarly changed from representante legal to representante legalmente designado.
- Note that the adjective incapacitated is no longer incapacitado, but incapaz.
End-point: new spelling
An apt term to wind up this blog post on terminology. Oxford Dictionaries says that end point is the correct spelling. Cambridge uses endpoint and Collins offers both alternatives. The new CT Regulation and Wikipedia are alone in using end-point as a noun.
In my last blog post, I said I’d explain how to align the new regulation in any European language pair and share my Spanish-English tmx alignment in this post. I haven’t forgotten. Here it is.
Taking note of this for my glossary :-). Thank you for all your work and for sharing it, Emma
Thanks so much for sharing this information, Emma. Very useful indeed!
Many thanks Emma. This is an incredibly useful post.
Thanks for the info Emma. Very useful as always!
Thank you very much for this, Emma. Extremely useful and important information.
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Art 74:”Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor’s obligations pursuant to this Regulation,…”
…nothing to do with the legally designated representative for consenting.
Yes, you’re right, Raquel. The sponsor’s legal representative is a different use case and the terminology remains unchanged.
The new term “legally designated representative” refers solely to a research subject’s representative.