The three-route classification test
The sponsor is responsible for classification. If the effect is unclear, the Commission Q&A recommends contacting the relevant national point of contact.
Yes: treat it as a substantial modification and submit it for assessment through the applicable Part I, Part II or combined route.
Yes: use the Article 81(9) non-substantial modification route. This updates CTIS without turning the change into an assessed substantial modification.
Do not create a standalone CTIS filing for it. Identify it in the cover letter of the next substantial modification and update the dossier when the submission scope includes the affected information.
Check the combined effect. Several individually minor changes can together amount to a substantial modification. A change also cannot be routed through Article 81(9) if it triggers other changes that are substantial.
What each route means in CTIS
| Route | When it fits | Assessment and timing | Part I and Part II scope |
|---|---|---|---|
| Substantial modification | Likely significant impact on safety or rights, or on reliability and robustness of data. | Assessed by the Member State authorities. The change follows the CTR substantial-modification procedure before implementation, except where separate urgent-safety rules apply. | Can be Part I only, Part II only, or Part I and Part II. Part II-only substantial modifications are handled per Member State. |
| Article 81(9) non-substantial modification | No likely substantial impact, but the update is relevant to supervision of the trial. | Not assessed as a substantial modification. The Sponsor Handbook states that it is applicable from the submission date. | Can cover Part I, Part II, or both. A Part II Article 81(9) submission can include multiple Member States concerned. |
| Other non-substantial change | No likely substantial impact and not relevant to supervision. Typical examples include typos or administrative corrections that do not change meaning. | No standalone CTIS application. Record it with the next substantial modification as applicable. | Update the affected dossier material when the scope of the later submission allows it. |
Classify the change, not the document type
The same document can support different regulatory routes. An Investigator's Brochure update can be substantial if it changes the benefit-risk assessment, while an annual update without significant changes can fall under Article 81(9). A protocol field being technically editable through the non-substantial-modification module does not make the underlying change non-substantial.
Denmark's February 2026 CTIS update expanded the data and document fields that can be edited through the non-substantial-modification module. That functionality changes what CTIS can technically accept, not the CTR classification test.
Choose the Part I or Part II scope after classification
Part I covers the common scientific and technical assessment. Part II covers Member State-specific aspects. For a substantial modification, select the dossier part affected by the change. For an Article 81(9) update, CTIS can likewise be scoped to Part I, Part II or both.
Do not use a broad scope merely because CTIS permits it. Update only the structured data and documents needed for the actual change, while preserving the complete assessment version where required.
Check open submissions before creating the draft
The Sponsor Handbook warns against creating an Article 81(9) draft while another draft exists because CTIS creates a new draft from the last authorised data. It also sets submission-compatibility rules for overlapping applications. Sequence the change against any open substantial modification, additional Member State application or other lifecycle submission before editing the dossier.
For a substantial modification, confirm that the affected Member State and dossier part are eligible for a new submission. For Article 81(9), confirm that no competing draft will overwrite or omit newer authorised information.
A practical source-check workflow
- Describe the proposed change and every downstream document or data field it affects.
- Apply the Article 2(2)(13) substantial-impact test to safety, rights and data reliability.
- If it is not substantial, ask whether the update is relevant to supervision under Article 81(9).
- Check the cumulative effect of related changes rather than classifying each item in isolation.
- Choose Part I, Part II or combined scope only after the regulatory route is clear.
- Review the current Sponsor Handbook submission-compatibility table before creating the CTIS draft.
- Use the CTIS document naming convention for replacement, tracked-change and other document versions.
- If the submission can trigger publication, run the CTIS transparency and redaction check before upload.
Official sources and resources
- European Commission Clinical Trials Regulation Questions & Answers, March 2026, especially section 3.1 on modifications.
- EMA CTIS Sponsor Handbook, version 6.4, updated 17 July 2026.
- CCMO: Types of modifications.
- Danish Medicines Agency: New functionalities in the CTIS module Non-Substantial Modification, 9 February 2026.
Last reviewed: 18 September 2026