Clinical trials are usually subject to many modifications after they have been authorised. Those modifications may relate to the conduct, the design, the methodology, the investigational or auxiliary medicinal product, or the investigator or clinical trial site involved.
Since different rules apply to the different types of modifications, it is important to distinguish between them. The currently valid document published by the Clinical Trials Coordination and Advisory Group (CTCAG) with questions and answers regarding Regulation (EU) 536/2014 contains a table in Annex IV that lists examples of substantial modifications (SM) and non-substantial modifications (NSM) as well as modifications in accordance with Article 81 (9) of Regulation (EU) 536/2014 (81.9 NSM). This table is not exhaustive, but it is helpful in classifying the modifications.
If the modifications have a significant impact on the safety or rights of the trial participants or on the reliability and robustness of the data generated in the clinical trial, they must be authorised in a procedure similar to the initial authorisation procedure. These "substantial modifications" (SM) also include the addition of a test site or the change of the principal investigator at a test site (see Chapter III of Regulation (EU) 536/2014).
The sponsor must provide contextual and scientific reasoning for the substantial modifications. General information such as "clarification" or "upon request of the authority" is not sufficient on its own. The specific changes must be highlighted in the documents by using track changes mode. The documents must be also submitted in a clean version for authorisation.
An application for authorisation of a substantial modification can only be made if the corresponding study has already been authorised and there is no other substantial modification being evaluated.
If a substantial modification becomes urgently necessary at a time when the evaluation process of a previous substantial modification is still ongoing, the sponsor has the option to withdraw the application that is already in progress. This allows the sponsor to submit a revised substantial modification in a timely manner.
If the modifications are so extensive that they require a completely new version of the documents, the modifications to the documents should be listed in an additional table. This allows for a summary of any repeated document changes. The new version of the documents is marked by a new date and a new version number.
Sponsors are strongly advised not to submit any non-substantial modifications during the request for information (RFI) phase of an ongoing assessment (initial, substantial modification, addition of a new Member State concerned) unless they are required as part of the RFI response.
Details of the application documents for substantial modifications can be found in Annex II to Regulation (EU) 536/2014.
In addition to substantial modifications, there are also modifications that are not "substantial" within the meaning of the word but are relevant for clinical trial monitoring by the affected Member States. These modifications are referred to as "Article 81 (9) modifications", in accordance with the location in the text of Article 81 (9) of Regulation (EU) 536/2014. They should be updated on an ongoing basis in the Clinical Trials Information System (CTIS).
For example, an amended Investigator's Brochure (IB) that has undergone an annual update without any changes to the safety, efficacy or benefit-risk assessment is known as an "Article 81 (9)" modification. This modification is relevant for the monitoring of the clinical trial and can be submitted on an ongoing basis.
A non-substantial modification in accordance with Article 81 (9) (EU) 536/2014 may only be submitted as such if it does not entail any additional changes that are to be regarded as substantial modifications. If there are several different modifications to be made in accordance with Article 81 (9), the group of modifications may well develop into a substantial modification and must then be submitted as such.
Finally, there are changes known as "non-substantial modifications" (NSM). These have no influence on the safety or rights of the trial participants or on the reliability and robustness of the data, nor are they relevant for the monitoring of the clinical trial. Non-substantial modifications (e.g. correction of typos and other administrative changes that do not affect the content and meaning of the information) should always be made within the framework of the next substantial modification that affects the part concerned. Non-substantial modifications must be listed in the letter requesting the substantial modification.
Updated: 20.08.2025
