Substantial amendments

Substantial amendments refer to amendments:

• Which change a local sponsor or principal investigator of the trial
• Which is likely to affect, to a significant degree:
  • The safety, or physical or mental integrity, of any participant of the trial
  • The scientific value of the trial
  • The conduct or management of the trial
  • The quality or safety of any investigational product used in the trial

Local sponsors should assess whether an amendment qualifies as a substantial amendment.

All substantial amendments must be submitted to us (for approval or acceptance of notification) prior to implementation. However, an exception may be made if the amendment is to protect trial participants against any immediate hazard to their health or safety (i.e. urgent safety measure). Any urgent safety measure taken should be reported to us as soon as possible and no later than 7 calendar days.

The sponsor of the clinical trial should also ensure that the details and rationale for the amendments are clearly described in the submission.

In addition, the sponsor is required to keep records of all substantial and non-substantial amendments to the trial, and provide such records to us if requested.

Supporting documents

Refer to our Guidance on Determining Whether an Amendment to a Clinical Trial is a Substantial Amendment348 KB for more details.

Submission should be done via Amend CTA/CTN/CTC module in PRISM (view sample online forms here276 KB and here634 KB).

Turn-around-time

Standard turn-around-time:

• Substantial amendments to CTA/CTC: 15 working days
• Substantial amendments to CTN: 5 working days

Serious breaches

A serious breach is a non-compliance to the principles of Good Clinical Practice, study protocol or the regulations, that is likely to affect, to a significant degree, either of the following:

• The safety, or physical or mental integrity, of any trial participant of a clinical trial.
• The scientific value of the clinical trial.

The local sponsor should submit a notification to us via PRISM (view sample online form264 KB) as soon as possible and no later than 7 calendar days after being aware of the serious breach.

Refer to our Guidance for Notification of Serious Breach299 KB for examples and more details on considerations in the reporting of serious breaches. 

Urgent safety measures

Urgent safety measures refer to actions taken by the local sponsor or the investigator, in order to protect any trial participants against any immediate hazard to their health or safety.

The local sponsor should submit a notification to us via PRISM (view sample online form264 KB) as soon as possible and no later than 7 calendar days after the urgent safety measure. Details should be given on the circumstances leading to the urgent safety measure.

Adverse events reporting

Local sponsors are required to report adverse events associated with therapeutic products, medicinal products or medical devices used in clinical trials.

Refer to adverse events reporting in clinical trials or our guidance538 KB for more information.

Other safety-related documents (e.g., annual/periodic safety report, development safety update report) may be submitted to us at the local sponsor’s discretion, unless otherwise requested by us.

Product defects and recalls

Manufacturers, importers and suppliers (including local sponsors) are responsible for the safety, quality and efficacy of their products. They should have systems and procedures in place to investigate, review and report product defects, and if necessary, promptly recall affected products.  

Refer to our Guidance on product defect reporting and recall procedures for therapeutic products and cell, tissue and gene therapy products408 KB for procedures and timelines related to product defect reporting and notification of product recall.

Updates to the investigator's brochure or new safety information

The local sponsor must notify us of all updates to the investigator’s brochure or new safety information as soon as it's available. 

Submission should be done via Amend CTA/CTN/CTC module in PRISM (view sample online forms here276 KB and here634 KB).

An email acknowledgement of receipt will not be provided for submission of updates to the Investigator’s Brochure or New Safety Information. If required, the system acknowledgement displayed on screen upon successful submission in PRISM may be retained as documentation of the submission to HSA.

Trial status reports

Trial status reports should be submitted by local sponsors every six months from the approval or acceptance date of CTA, CTN or CTC, up until the completion or termination of the trial. The report is due within 14 calendar days of each due date.

We may request for status updates at any time in addition to the above.

Definitions of trial status and recruitment status is found in our Guidance for New Applications and Subsequent Submissions452 KB. 

Submission should be done via Clinical Trial Status Report module in PRISM (view sample online form17 KB).

Suspension, termination or completion of a clinical trial

Notification of suspension or termination should be done within 15 calendar days from trial suspension or termination, while notification of trial completion should be done within 30 calendar days from trial completion.

Trial completion is generally defined as the achievement of Last Patient Last Visit (LPLV). For multi-national clinical trials, trial completion refers only to the LPLV for the local trial sites.

For clinical trials with remote follow-up after LPLV, trial completion will be the end of remote follow-up (i.e., last patient last contact).

Notification should be done through the Clinical Trial Status Report module in PRISM (view sample online form17 KB).

Final clinical trial reports

The local sponsor should submit the final report of the clinical trial within one year of the study's completion, unless otherwise agreed by us.

You may refer to ICH Guideline E3: Structure and Content of Clinical Study Reports for more information on the structure of the final report.

For investigator-initiated clinical trials, a publication of the clinical trial may be submitted to us in place of a final report. 

CRM Non-compliances

Local manufacturers, importers and suppliers (including trial sponsors and investigators) should notify us of any CRM related non-compliances using the CRM Non-Compliance Form. 

Other submissions

Updates or changes to the following should also be submitted:

• CRM notification (e.g. changes to CRM quantity, research sponsor, clinical research)
• Information to be published in the Clinical Trials Register
• Regulatory status of the trial in other countries (e.g. clinical hold or non-approval by regulatory authority)

Turn-around-time

Standard turn-around-time: 5 working days

• Acknowledgement email for application form amendments to CRM notification will be sent immediately upon submission.