INSTRUCTIONS FOR REPORTING SERIOUS BREACHES (SB) OF GOOD CLINICAL PRACTICE AND TRIAL PROTOCOLS

Local regulatory requirements

The Regulation on Clinical Trials of Medicinal Products in Human Medicine (“Official Gazette of the Republic of Serbia”, No. 51/2022, 65/2023, 86/2023, 97/2024) contains a requirement for notification of serious breaches of Good Clinical Practice (GCP) or clinical trial protocols (CT):

This implies a definition of the term itself: in Article 2, Paragraph 1, Item 35): “a serious breach (Serious Breach) is a deviation from the Protocol, or the guidelines of Good Clinical Practice and is a deviation that is considered to affect the safety of subjects or their mental integrity, as well as the consistency of data obtained in a clinical trial”

Also, among the obligations of the sponsor in Article 26 is stated:

Paragraph 1, item 23): “reports to the Agency a serious breach that occurred as a result of a deviation from the Protocol, or the guidelines of Good Clinical Practice, without delay, and no later than seven days from the date of learning about the serious breach, which is reported electronically on the form that the Agency publishes on its website”.

A Serious Breach is submitted via the RIMS application using the aplication “REPORT OF SERIOUS Breach (SB) of good clinical practice or clinical trial protocol“, on the official form for reporting a serious breach (exact name – REPORT OF SERIOUS Breach (SB) OF GOOD CLINICAL PRACTICE OR CLINICAL TRIAL PROTOCOL (CT)), which is available on the Agency’s website (in the section Regulations – Human Medicines – Forms, and also on the page Good Clinical Practice (GCP) – Notification of serious breaches, together with these Instructions).

The requirement is implemented through local regulations with the aim of

providing safety to subjects in CT by informing the competent authorities about serious violations that may occur during the conduct of the trial, in order to take appropriate action in response to the violation

and/or

obtaining information regarding serious violations in order to assess future CT approval submissions and registration submissions that include data from the CT affected by the serious violation.

Purpose of this guidance

reviewing the practical arrangements for the notification/reporting of SB
providing advice on what should and should not be classified as a “serious violation” and what must be reported
reviewing the possible actions that the Agency can take in response to a notification/reporting of

How to report a serious violation

Who should report SB?

Reporting is carried out by the sponsor or the sponsor’s authorized representative in the Republic of Serbia who has been assigned this obligation through a Letter of Authorization. The Contract Research Organization (CRO), as an authorized representative of the sponsor, is defined by the Law on Medicines (Article 71) and the Regulation (Article 27). However, in the interest of subject safety, reporting should not be delayed by invoking strictly delegated obligations of the sponsor.

When should the report be made?

Within 7 calendar days of the sponsor receiving information about the breach. If notification is delegated to a sponsor representative (CRO), the 7 calendar day period applies to the authorized representative
If the sponsor retains the notification function, it is recommended that the agreement/authorization between the sponsor and other parties involved in the trial (e.g. CRO, investigators) should provide that, in case of the first indication of a serious breach (as defined in the Regulation), the sponsor is immediately notified so that the sponsor, in turn, can fulfill its obligations under the regulation. In this case, the time is counted from the time the sponsor first receives information that an SB has occurred
If the sponsor receives clear and unambiguous evidence describing an SB (as defined by the regulation), the sponsor is expected to first report the case to the Agency, within 7 calendar days, then investigate the case and take action immediately or after notification/reporting. In this case, the sponsor should not wait to receive all the details of the SB before the initial report.
The sponsor should ensure, through a written agreement, that all parties involved in the conduct of the clinical trial, in accordance with their responsibilities, immediately report any events that could meet the definition of a serious violation.
In the case of the principal investigator involvement, the protocol may replace the written agreement/contract. Documented training of the principal investigator and study team members on this topic should be maintained in the Clinical Trial Master File (CTMF), and the sponsor should provide the principal investigator with a dedicated, unique email address and telephone number for such communication, which can be accessed at all times. The sponsor should review the information received and should make every effort to demonstrate that the violation is serious before submitting it to the Agency. However, any assessment by the sponsor to confirm that a serious violation has indeed occurred should not extend the 7 calendar day reporting period.
Updates to the data related to a serious breach may be made whenever additional information becomes available. If an investigation or corrective and preventive action is ongoing at the time of reporting the serious breach, it is acceptable to provide plans with anticipated deadlines for completion. In such cases, the initial report should indicate when the above is expected to be completed and which follow-up reports will be submitted via RIMS and when.
A pragmatic approach should be used in the timing of reporting the breach. The Agency will review the notification process during the conduct of the GCP supervision and any delay in notification/reporting will be considered as non-compliance. If there is any doubt about how and when to report, contact the Agency (Center for Human Medicines, Clinical Trials Control, emails available on the Agency’s website named Good Clinical Practice (GCP)).

Who should be notified?

Notification of SB is reported to the Agency
It is recommended to use the form provided by the Agency and available on the Agency’s website. This ensures uniformity of information submitted to the Agency. If such a form is not used, then the written report should clearly state everything related to the SB and that the document, in fact, confirms the SB. The form allows the submitter to provide a description at the length they consider appropriate.
The sponsor may initially contact the Agency by telephone to discuss the SB and the necessary follow-up information (follow up in writing) within 7 days of the date of initial notification.
It is recommended that the sponsor inform the investigators about the SB This communication facilitates the implementation of corrective and preventive actions (CAPAs).

Note:

It is not need to wait for ALL information to be received, it is acceptable to update information over time. If the root cause analysis related to the SB or CAPAs is ongoing at the time of reporting the SB, it is acceptable to indicate a plan to resolve the SB with projected timelines for completion of the SB. In this case, it should be indicated that an initial report will be submitted as well as follow-up reports with an indication of the period. Follow-up reports should be in writing (you can also use the above template as a follow-up) with a clear acknowledgement that it is a follow-up report.

Identification of serious violations – points for consideration

Protocol and GCP deviations usually occur in CT. Most of these examples are technical deviations that do not result in harm to the subject or do not significantly affect the scientific value of the reported trial results. Such cases should be documented (ISF, CTMF), all with the aim of implementing appropriate measures (CAPAs) to be taken by the sponsor. Deviations should also be included and considered when drafting the final report because they may have an impact on the data analysis. However, not every protocol deviation should be reported to the Agency as an SB.

What should be reported?

Any serious violation of:

(a) the terms and principles of the GCP related to the given trial; or

(b) the protocol of the given trial

For regulatory purposes, a serious breach is any breach that is likely to have an effect to a significant degree on:

(a) the safety or physical or mental integrity of the subjects (should refer to subjects of that trial in the Republic of Serbia); or

(b) the reliability and validity of the data as well as the scientific value of the given CT.

The assessment of whether a breach will potentially have a significant impact on the scientific value of the trial depends on various factors, for example, the design of the trial, the type and volume of data affected by the breach, the overall contribution of the data to the key analysis parameters, the impact on the exclusion of data from the analysis, etc.

The assessment of the impact of the breach on the scientific value of the data is the responsibility of the sponsor.

The assessment should be documented, as should the sponsor’s decision-making process; this may be subject to review during the conduct of Agency oversight.

The decision as to whether a breach is likely to affect the reliability and validity of the data in the CT depends on a number of factors, for example: the study design, the type and extent of data affected by the breach, the overall contribution of the affected data to the key analysis parameters, the impact of excluding data from the analysis, etc. It should be noted that taking mitigation actions to remediate the occurrence of serious breaches does not negate the fact that a breach has occurred and should be treated in accordance with legal requirements.

Similarly, if systematic and/or significant misdosing has occurred, this would still meet the criteria for a serious breach regardless of whether subjects suffered adverse adverse reactions as a result of that misdosing.

It is the sponsor’s responsibility to conduct a thorough root cause analysis to identify the cause of the serious violation and to assess the impact of the violation on the reliability and validity of the data as well as the impact on the safety and/or rights of the subjects in the trial.

This assessment should be documented, as should the consistency of the decisions and actions taken by the sponsor and may be reviewed during GCP supervision of the Agency.

Where sponsor tasks are delegated to specific parties, and there is a disagreement in the classification/assessment of the violation between the sponsor and the specific delegated party that does not report the serious violation, specific communications between the sponsor and the delegated party should be documented. In particular, their individual views on whether or not a violation occurred should be recorded. In addition, the sponsor’s reasons for not pursuing notification, taking into account the views of the delegated party, should be documented.

Deviations from the protocol, Good Clinical Practice (GCP) and/or local regulations may occur in clinical trials where they are considered important and, as defined by the ICH E3 guideline on the structure and content of clinical study reports, should be described in the Clinical Study Report (CSR). It is important to note that significant deviations, as defined in the ICH guideline E3– questions and answers (R1), are not equivalent to the definition of a serious violation and therefore a significant deviation is not necessarily a serious violation and vice versa. However, all serious violations should be included in the appropriate CSR. Not every (important) deviation from the protocol needs to be reported via RIMS as a serious violation.

See Appendix I of this document for further information regarding the Agency’s expectations regarding the details of the SB application; this may assist in the decision regarding the submission of a SB notification. Appendix II contains some examples (situations) that may be considered as a breach depending on their content. This list is not exhaustive as there are other situations that may be presented to the SB. It is the responsibility of the sponsor to assess the information and ensure adequate reporting.

Individual Responsibilities

The Sponsor:

Should establish a process/procedure to address SB reporting as part of regulatory requirements. This should include:

SB assessment [e.g. assessment of the deviation/violation by the sponsor or the party delegated by him, whether it is an isolated/systematic incident, what is the risk to the subject(s) or the credibility of the data, etc.]
management of serious violations should be included in the sponsor’s quality system, as a separate standard operating procedure and/or recorded in the protocol
upon receipt of the information, an assessment of the violation should be carried out to determine whether it is “serious” (i.e. assessment of the deviation/violation, isolated/systematic incident(s), harmed or exposed trial participants, credibility of the data, etc.)
an investigation of the serious violation, including a root cause analysis (this may sometimes be in the process of reporting) should be carried out
corrective and preventive actions should be identified (this may be ongoing at the time of reporting)
reporting to the Agency
compliance with 7-day time reporting.

A deficiency in the sponsor’s quality system or failure to report on SB may result in subsequent action by the Agency in terms of conducting GCP supervision.

Investigator:

The investigator should be familiar with the process for identifying and notifying a serious violation directed to the sponsor. Accordingly, it is desirable to have a process that will fully address the management of serious violations:

this may be, formally speaking, a standard operating procedure (SOP), an explanation in the Protocol or study-specific instructions
furrther, personnel in the study team or service providers delegated by the principal investigator/institution must be able (trained) to identify the occurrence of a serious violation or a potentially suspected serious violation;
if there is a suspicion of a serious violation, it is necessary to immediately report it to the sponsor or delegated party, via the contacts (email or phone) provided by the sponsor or delegated party

Particular attention should be paid to the measures to be taken if the sponsor does not report the SB to the Agency within the prescribed period (reasonable steps are required by the investigator in order to satisfy the regulatory requirement – e.g. will he continue working in the given CT? Will he report to the Agency? Does he follow local regulations for the implementation of CT? – this is what the investigator is required to know because his/her further engagement in the given CT depends on it.

Service providers

Service providers (including service providers delegated by the principal investigator/institution):

should have a written process/procedure for identifying (suspected) serious breaches
should immediately notify to the sponsor or delegated party about the (suspected) serious breach, in accordance with the contractual agreements provided and via the contacts (email or telephone) provided by the sponsor or delegated party.

Steps taken by the Agency

Upon receipt of an SB notification, the Agency will assess the notification and may take a number of actions, depending on the nature of the SB and its potential impact. In general:

upon notification, the Agency reviews the reported SB data
determines whether the reported situation is indeed a serious breach of the CT
analyzes the SB based on the information received or proposes an action required by the situation.
Next, the Agency will decide:
whether the nature of the SB requires only to be recorded and processed – no further action (the case may be reviewed during some future Agency supervision);
whether it should request additional information from the sponsor/CRO; if the information provided during the initial notification is not sufficient to assess the impact of the SB, then additional information will be requested;
whether the SB reporting must be forwarded to other stakeholders (Ministry of Health, Ethics Committee, etc.);
on further actions (e.g. potential trigger for announcing future surveillance);
on informing the Ministry of Health about the possibility of temporary or permanent suspension of the CT.

when all activities related to the SB assessment have been successfully completed, the Agency closes the case.

Retention of documentation/information on SB:

Depending on the organization of sponsor/CRO and their quality system, documentation on the identification and reporting of the SB will also be retained. Regardless, the minimum documentation would be a copy of the described case that would be in the master file (CTMF).

Circulation of SB information:

Internal: internal communication for the archiving of SB documents depends on the needs of the parties in the CT, in accordance with the operational procedures and in accordance with the responsibilities of individual structures for decision-making and reporting to the Agency (e.g. Medical Department, Regulatory Department, Quality Assurance, Sponsor Management, etc.)

External: may involve the Agency or other stakeholders (where required by local regulations)

However, it is important that the SB notification is circular; make it available to relevant entities for the inclusion of adequate information in the final study report or publication. Notification of SB related to a specific site should also be available so that an assessment can be made for the subsequent selection of the site or other CTs (avoid non-compliant sites in the future).

Appendix I

Expectations for specific situations:

Should a breach of Good Clinical Practice or Protocol who leads to death, hospitalisation or permanent disability be reported as a SERIOUS Breach (SB)?

If serious adverse events (SAEs) or serious unexpected reactions (SUSARs) arise from a breach of the terms and principles of the GCP or a breach of the Protocol, then they will be part of the serious breach. However, it should be emphasised that not every SAE or SUSAR will be routinely classified as an SB.

Also, submitting a notification of a SB to the Agency does not relieve the obligation to report SUSARs to the Agency. If the SB requires a revision of the Protocol, a request for approval of a substantial amendment must be submitted to the Agency (Clinical Trials Department).

In case of SB which results in temporary/permanent discontinuation of the trial, it is necessary to submit to the Agency (Clinical Trials Department) a notification of the type of discontinuation (temporary/permanent) as well as an amendment that would allow for subsequent approval/consent regarding the continuation of the trial by the Agency (in case of temporary discontinuation).

Should a failure to report serious adverse events or SUSARs in accordance with the regulation be reported as a SB?

If the failure results in a significant risk to the safety of the subjects then this constitutes a SB, for example, inadequate safety reporting in dose escalation studies may influence decision-making when increasing the dose to the next dose level.

Should a permanent or systematic non-compliance with the GCP or Protocol be reported as a SB?

If the non-compliance has a significant impact on the integrity of the subjects or the scientific value of the data, then it constitutes an SB. For example, the widespread and uncontrolled use of Protocol waivers (sponsor documents that allow deviations from the Protocol when assessing the criteria for entering patients into a CT) that harm subjects or that significantly affect the scientific value of the trial. Or, if the investigator repeatedly fails to reduce the dose of the study drug or to stop dosing under certain conditions dictated by the Protocol (e.g., abnormal laboratory results).

Should a failure in the administration of the study drug(s) be reported as an SB?

This would constitute an SB if the failure results in a significant risk to subjects or the trial data being compromised. If the SB occurs as a result of a defect in the investigational drug, then the defect report should be reported to the Agency (Clinical Trials Department, part related to the assessment of the quality of the investigational drug), along with the SB reporting in a regular manner.

Should fraud related to investigator reports in a CT or data recording be reported as an SB?

The general expectation is that if a sponsor becomes aware of fraud, it should report it as an SB.

The Agency encourages reporting of possible fraud at trial sites in the RS, even though there is no regulatory requirement, as soon as the sponsor first receives the information. The reason for this may be that, although the fraud occurred at one particular trial site and may not have a significant impact on the integrity of the subjects and the scientific value of that CT, the Agency still wants to assess the impact on other CTs or subjects/patients from that trial site.

If the fraud constitutes an SB and did not occur at sites in the RS, and the given CT is being conducted in the RS, then a notification of the SB should be submitted to the Agency if the fraud significantly affects the integrity of the subjects or the scientific value of the trial data. In this case, the CRO or sponsor should notify all sites in the RS.

For CTs that are ongoing in the RS, should an SB that occurred in study sites located in other countries be reported, and that concern that CT?

If an SB of a given CT occurred in another country, and the same trial is also being conducted in the RS and could potentially impact subject safety or the credibility of data in the RS, then this requires notification to the Agency. For example:

The cause of the SB may be the death of a subject associated with incorrect administration of the investigational drug resulting from incorrect instructions for reconstitution and dosing of the investigational drug in the Protocol. This should be recorded and reported to the Agency in the form of an SB.

In relation to the above example, it is possible for the sponsor to introduce urgent safety measures (USM) in order to minimise the cause that led to the If the sponsor has to change the way the CT is conducted (e.g., stop the recruitment of subjects for a while) or to stop the CT, then it must send a notification to the Agency about the introduction of the USM that it needs to take, along with regular notification to the Agency about the existence of the SB.

If a SB is identified in study sites outside the RS, which may significantly affect the data in the CT or the integrity of the subjects in the RS (e.g., the data would be used for the registration of a drug in the RS), then that SB should be reported to the Agency.

Appendix II

*Reported by*	*Reporting details*	*Is it SB or not?*
Sponsor	The subject received doses of the study drug that were not in accordance with the dosing regimen in the Protocol (e.g., the study drug was administered in accordance with some other study Protocol)	YES, there is a significant impact on the safety, physical or mental integrity of the subject.
Sponsor	The subject was receiving the study drug, but was assigned to a different arm in the CI (treatment arm). Further, several months later, it was observed that subjects in the entire treatment arm were receiving the study drug three times a day instead of once a day.	YES, • There is an impact on the safety, physical or mental integrity of the subject, or the scientific value of the study • The problem systematically and persistently led to a consistent violation of the terms and principles of the GCP, Protocol
Sponsor	One subject received 6 additional doses of study drug. The subject was supposed to receive the study drug on days 1 and 8, but instead received the drug from days 1 to 8 (on all days). The subject experienced an SAE as an outcome.	YES, There is an impact on the safety, physical or mental integrity of the subject, or the scientific value of the study.
Sponsor	Subject was taking expired study drug two days prior to dosing. Subject had no adverse events and this issue did not impact the credibility of the data.	NO, there is no impact on the safety, physical or mental integrity of the subject or the scientific value of the study. This is an isolated episode and a detailed CAPA has been implemented.
Sponsor	A temperature excursion where the study drug was stored was reported	YES, if the situation was not managed and subjects were dosed with study drug that was assessed as unstable, it could result in harm/potential harm to the subjects. NO, if the issue was identified, it was managed properly – study drug was quarantined as needed and there is a statement from the sponsor’s representative (QP person) that there is no impact on subject safety and data integrity.
Спонзор	Multiple issues have occurred with the Interactive Response Technology (IRT) system for dispensing study medication, resulting in no medication being available at the sites during the study visit.	YES, there is an impact on the safety, physical or mental integrity of the study participant and this issue is leading to a consistent violation of the principles and conditions of the GCP and the Study Protocol, despite the implementation of CAPA.
Sponsor	The sponsor identified two separate events within a single system. First, with the consenting process, and then with potential fraud during recruitment and consenting. One of the studies included pediatric subjects.	YES, this may even lead to enforcement action against the participants who caused the fraud.
Sponsor	During the monitoring visit, suspicions arose regarding the data in the source data for several subjects, which consequently led to subjects being eligible for study entry without explanation. Sponsor-disputed audits and other data changes were recorded without explanation, potentially impacting data integrity. Follow-up reports sent to the Agency confirm the sponsor’s concern about the consenting issue and the change in documentation without written explanation.	YES Note: not all information was provided during the initial SB application; the sponsor provided only supporting information.
Sponsor	The subject was in an emergency room where the staff attempted to contact the center where the patient was participating in the trial (using the phone number on the Emergency Card provided to the subject). The trial center (i.e., the pharmacy distributing the study drug) was unable to unblind the code through which the subject received the drug in a timely manner. As a result, the subject withdrew from the trial, dissatisfied that the center was not available in a situation requiring emergency care.	YES, this has a significant impact on the subject’s harm if unblinding could affect the course of further treatment.
CRO	The cohort has invalid blood samples because they were processed incorrectly. As a result, one of the secondary endpoints cannot be met. Therefore, a substantive amendment has been issued requiring more subjects to be recruited in order for the sponsor to meet the endpoint. As a result of the above errors, subjects were dosed unnecessarily.	YES
CRO	The investigator failed to report an individual SAE as required by the Protocol (there was evidence of repeated investigator training).	NO If this did not occur in other subjects and they were not at risk and if it was not a systemic or persistent problem. In some cases, failure to report a SUSAR may have a significant impact on subjects. The excess information and content should allow the potential impact to be adequately assessed.
Identifying by regulatory inspection	The trial site failed to reduce or discontinue the study drug dose in response to individual laboratory parameters, as per the protocol. This occurred in multiple subjects within a year, despite the monitor identifying the first two cases. The subjects were at increased risk of thrombosis.	YES
Identifying by regulatory inspection	A potential SB was identified but not reported (documentation submitted by the sponsor indicates that there may have been potential fraud at the site, reuse of data from an earlier period of the study). The sponsor investigated the case and concluded that it was a genuine error, not fraud.	NO, in this case. However, even if it was identified as fraud that affected data integrity, it was not reported to the Agency within the time frame required by the regulations.
Sponsor	New versions of the Informed Consent Form and the Subject Information Leaflet have been developed, but at one center this was not provided to subjects, subjects received it approximately 2-3 months after approval.	NO, if it is not a systemic or persistent problem and if it does not harm subjects due to the delay. YES, if there is a significant impact on subject integrity (e.g., the documents contain key safety information that was not provided to subjects for review in a timely manner).
Agency (CT Dpt.)	A substantial amendment due to changes in dosing in the CI (following an SAE that occurred in the initial subject) has been submitted to the CI Evaluation and Approval Department for approval; the trial is being conducted for the first time in humans. The sponsor has temporarily stopped the trial and, after internal assessments, has confirmed that the SAE is not related to the investigational drug. The sponsor did not notify the CI Department of the “urgent safety measures” (USM) to be implemented, nor did it report the SAE as a potential SUSAR.	Yes
Sponsor	Deviation regarding the date of the visit. A common and frequent deviation in the CI.	NO, it is a minor protocol deviation, it does not meet the criteria for notification.