This is a ready-to-use form for assessing whether a change to a clinical trial, including a change to the IMP’s manufacturing, specification, or control strategy, is a substantial modification requiring authorisation before implementation. Replace every <<FILL: ...>> placeholder, set your own document numbers, and route it through your normal change control. A filled specimen follows. Verify the current text of the Clinical Trials Regulation and your competent authority’s guidance before relying on this assessment. This content is educational reference, not regulatory or legal advice.
Document control header
| Field | Entry |
|---|---|
| Document title | Clinical Trial Modification Impact Assessment |
| Document number | <<FILL: FORM-ID, e.g. REG-FRM-027>> |
| Version | <<FILL: version>> |
| Effective date | <<FILL: effective date>> |
| Trial identifier | <<FILL: EU trial number / IND number>> |
| Change control reference | <<FILL: linked change control record>> |
1. Describe the change
| Field | Entry |
|---|---|
| Change description | <<FILL: plain-language description>> |
| Change category | <<FILL: specification / manufacturing process / analytical method / labelling / protocol / other>> |
| Reason for the change | <<FILL>> |
| Data supporting the change | <<FILL: batch data, method validation, stability data, etc.>> |
2. EU assessment: the Article 15 impact test
Regulation (EU) No 536/2014, Article 15, defines a substantial modification as one 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 trial. Answer each question on the evidence, not on a preference to avoid the Article 16 authorisation wait.
| Question | Answer | Basis |
|---|---|---|
| Could this change plausibly increase risk to subjects (for example, a different impurity profile, a different dose delivered, a different storage condition in the field)? | <<FILL: Y/N>> | <<FILL>> |
| Could this change plausibly affect subjects’ rights (for example, consent-relevant information, a protocol procedure)? | <<FILL: Y/N>> | <<FILL>> |
| Could this change plausibly affect the reliability or robustness of the data the trial will generate (for example, a method change that is not yet shown equivalent, a specification change affecting comparability across trial phases)? | <<FILL: Y/N>> | <<FILL>> |
| Is there a specific, documented reason supporting a “no” on every row above (not merely the absence of an obvious risk)? | <<FILL: Y/N, state the reason>> | <<FILL>> |
3. Classification
| Field | Entry |
|---|---|
| Classification | <<FILL: Substantial / Non-substantial>> |
| If substantial: Article 16 application required before implementation | <<FILL: Y, with submission date>> |
| If non-substantial: recorded in change control, no pre-implementation authorisation required | <<FILL: Y, with change control reference>> |
| Classified by (name, role, date) | <<FILL>> |
| Reviewed by Regulatory Affairs (name, date) | <<FILL>> |
4. US parallel assessment (if the trial also runs under an IND)
| Question | Answer |
|---|---|
| Does the change significantly affect the safety of subjects? | <<FILL: Y/N>> |
| Does the change significantly affect the scope of the investigation? | <<FILL: Y/N>> |
| Does the change significantly affect the scientific quality of the study? | <<FILL: Y/N>> |
| If any answer is yes: protocol or information amendment submitted under 21 CFR 312.30 / 312.31 before implementation | <<FILL: Y, with submission reference>> |
| If all answers are no: change documented, reportable in the next annual report | <<FILL: Y, reference>> |
5. Implementation gate
Do not implement this change until:
- For a substantial modification: the Article 16 authorisation (or, for the US, the required amendment) has been granted or submitted per the applicable rule.
- The product specification file, the IMPD/IND, and the released-against specification are updated and reconciled.
- Already-manufactured and already-released material is assessed for impact (does the change apply retroactively, and if so, to which batches).
6. Acceptance criteria
- The classification follows directly from the answers in Section 2 or 4, not from a predetermined preference for the faster path.
- A substantial modification is never implemented before its authorisation.
- A non-substantial change is still recorded, with rationale, in change control.
- The IMPD/IND and the product specification file are updated in step with the classification decision.
7. References
Regulation (EU) No 536/2014, Articles 15 and 16. 21 CFR 312.30 (protocol amendments) and 312.31 (information amendments).
Confirm the current text and any implementing guidance before relying on this classification.
8. Approvals
| Role | Name | Signature | Date |
|---|---|---|---|
| Preparer (CMC / Regulatory Affairs) | <<FILL>> | ||
| QA reviewer | <<FILL>> | ||
| Approver (Regulatory Affairs head) | <<FILL>> |
Filled specimen
A sponsor tightens the related-substance A limit from NMT 0.5% to NMT 0.3% ahead of Phase 2, based on six clinical batches observed in the 0.05 to 0.18% range and a now-validated method.
| Question | Answer | Basis |
|---|---|---|
| Could this change plausibly increase risk to subjects? | N | The tightened limit is well within the range already qualified by the GLP toxicology batches; subjects are exposed to less impurity, not more. |
| Could this change plausibly affect subjects’ rights? | N | No consent-relevant or procedural change. |
| Could this change plausibly affect the reliability or robustness of the trial data? | N | The method is now validated per ICH Q2(R2); tightening based on validated-method data on six batches does not change what the trial measures. |
| Documented reason for “no” on every row | Y | Toxicology coverage margin, method validation report REF-2026-114, and the six-batch data summary are attached. |
Classification: Non-substantial. Recorded in change control CC-2026-0871; no Article 16 application filed. The product specification file and the IMPD were updated the same week, and the released-against specification moved to the new limit only after that update was confirmed, not before.
Common inspection findings this form prevents
- A specification tightening implemented and released against before the IMPD was amended to match it.
- A change classified non-substantial with no documented basis, so a competent authority cannot tell whether the Article 15 test was actually applied or simply assumed.
- A US trial’s protocol change implemented without checking whether it met the 312.30 significance threshold for pre-implementation submission.
How to adapt this form
- Attach the underlying data (batch summaries, validation reports, risk assessments) referenced in Section 2 rather than relying on the summary answer alone.
- If your trial runs in multiple regions, confirm this form’s classification against each region’s own modification rules; “non-substantial” in one framework does not automatically carry over to another.
- Route a genuinely close call to Regulatory Affairs and your competent authority contact rather than defaulting to non-substantial.