What is it? Why is it important?

A protocol amendment is an implemented change to an approved protocol during study conduct (e.g. approved by Ethics Committee (EC) and if applicable Regulatory Authorities (RA) such as Swissmedic and FOPH).


An amendments can either be:

  • Substantial, or
  • Non-substantial


Studies must be conducted in compliance with an EC/RA approved protocol. Still, due to problems or situations encountered during study conduct, a protocol amendment might become necessary.


Consequently, a substantial amendment must be submitted and approved by EC/RA prior to implementation. Exceptions are safety amendments that require the implementation of protective measures (e.g. risk control-measures) in order to protect study participants. 


Non-substantial amendments are notified to:

  • RA as soon as possible
  • EC in the annual safety report


Examples where a protocol amendment might become necessary:

  • New scientific evidence becomes available requiring adaptations in study aim, safety concerns, statistical study plan
  • Data collection is inadequate requiring the collection of additional data and or material (e.g. additional blood samples, questionnaires)
  • Participant recruitment is too slow requiring changes or adaptations of study methods, design, procedures (e.g. inclusion of additional study sites, adaptations of inclusion/exclusion criteria, number of recruited participants)
  • Fluctuations in study staff requiring changes in responsibilities (e.g. substitution of Site-INV)

What do I need to do?

As a SP-INV and Site-INV, based on the ongoing evaluation of your study decide whether an amendment is necessary.

  • Prepare amended documents and include the SP-INV`s justification for a required substantial amendment
  • In the event of a safety amendment, immediately implement protective measures and inform the EC and as applicable RA
  • Wait for EC/RA approval prior to implementing any substantial amendments
  • Notify EC of any non-substantial amendment in the annual safety report
  • Notify the RA of any non-substantial amendments as soon as possible, and include them in the annual safety report
  • For every protocol amendment, evaluate whether changes to the PIS/ICF would also be required (PIS/ICF amendments)


Except for safety amendments, a substantial protocol amendment should be well thought through as delays in study conduct are expected (e.g. EC requires 30 days deliberation for mono-, and 45 days for multi-centre studies)


Substantial amendments that are subject to Swissmedic approval, include in particular changes:

  • To the IMP, the route of administration, dosage form or dose administered
  • Based on new preclinical or clinical data that may affect the safety of the product
  • To the manufacturing of the IMP that may affect the safety of the product

Where can I get help?

Your local CTU can support you with experienced staff regarding this topic

External Links

Swissethics – see in particular

  • Template annual safety report
  • Notification of significant and other changes to the EC


ICH GCP E6(R2) – see in particular guidelines

  • 1.44 Protocol definition
  • 1.45 Protocol Amendment definition
  • 4.5 Compliance with protocol
  • 6 Clinical trial protocol and protocol amendment(s)


ISO 14155:2020 Medical devices (access liable to cost) - see in particular sections

  • 6.4 Clinical investigational plan (CIP)
  • 7.5.1 Amendments
  • 10.5 Informed consent procedure
  • 10.6 Compliance with CIP
  • Annex A Clinical investigational plan

Swiss Law

ClinO – see in particular articles

  • Art. 29, 34, 55. Changes

HRO – see in particular article

  • Art. 18 Changes
  • CIP – Clinical investigational plan
  • ClinO – Clinical Trials Ordinance
  • CTU – Clinical Trials Unit
  • EC – Ethics Committee
  • EC/RA – Ethics Committee / Regulatory Authorities
  • HRO – Human Research Ordinance
  • ICF – Informed Consent Form
  • ICH-GCP – International Council for Harmonisation - Good Clinical Practice
  • IMP – Investigational Medicinal Product
  • ISO – International Organization for Standardization
  • PIS – Patient Information Sheet
  • RA – Regulatory Authorities
  • Site-INV – Site Investigator
  • SP-INV – Sponsor-Investigator
Conduct ↦ Management ↦ Amendment ↦ Protocol

Provides some background knowledge and basic definitions

Basic Protocol
Basic Statistics
Basic Monitoring
Basic Drug or Device

Starts with a study idea

Ends after having assessed and evaluated study feasibility

Concept Protocol
Concept Statistics
Concept Drug or Device

Starts with confidence that the study is feasible

Ends after having received ethics and regulatory approval

Development Protocol
Development Statistics
Development Drug or Device

Starts with ethics and regulatory approval

Ends after successful study initiation

Set-Up Protocol
Set-Up Ethics and Laws
Set-Up Statistics
Set-Up Quality and Risk
Set-Up Drug or Device

Starts with participant recruitment

Ends after the last participant has completed the last study visit

Conduct Protocol
Conduct Statistics
Conduct Drug or Device

Starts with last study visit completed

Ends after study publication and archiving

Completion Protocol
Completion Statistics
Completion Drug or Device
Current Path (click to copy): Conduct ↦ Management ↦ Amendment ↦ Protocol

Please note: the Easy-GCS tool is currently under construction.