Guidance

Clinical trials for medicines: collection, verification, & reporting of safety events

Guidance on the collection, verification, and reporting of safety events in clinical trials of an investigational medicinal product.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 25 June 2025

This guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025.

These amendments come into force on 28 April 2026.

Until this date, this guidance is in draft and should only be used to support sponsors in preparing for the implementation of the new regulations. Please see Clinical trials for medicines: apply for authorisation in the UK and Clinical trials for medicines: manage your authorisation, report safety issues for the guidance that should be followed prior to 28 April 2026.

We welcome your feedback on the new draft guidelines.

Legal status of this guidance

The following guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004 (“the Clinical Trials Regulations”), as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025. These amendments come into force on [implementation date]. For assistance in determining whether a clinical trial is within the scope of these Regulations, see Is it a clinical trial of a medicinal product? (please note that this algorithm will be updated in due course). Please note that the requirements outlined in this guidance still apply where the clinical trial is a notifiable trial that received automatic authorisation from the licensing authority.

Part 2 of Schedule 1 to the Clinical Trials Regulations requires that the investigator and sponsor have regard to all relevant guidance with respect to commencing and conducting a clinical trial. Investigators and sponsors (and any individual or organisation they delegate trial-related activities to) must, therefore, ensure that they are fully aware of the information within this guidance and act accordingly to achieve and maintain regulatory compliance.

In addition, the following guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are also considered relevant guidance and should be consulted:

• Clinical safety data management: definitions and standards for expedited reporting (E2A)
• Development Safety Update Report (E2F)
• Good Clinical Practice (E6(R3))
• General Considerations for Clinical Trials (E8(R1))
• A selective approach to safety data collection in specific late-stage pre-approval or post-approval clinical trials (E19)

Definitions

This guidance addresses the collection, verification and reporting of safety events which occur in a clinical trial falling within the scope of the Clinical Trials Regulations.

The definitions contained in the Clinical Trials Regulations also apply in respect of this detailed guidance.

Investigator: An investigator is defined as per regulation 2(1) of the Clinical Trials Regulations as follows: in relation to a clinical trial, the health care professional who is responsible for the conduct of that trial at that trial location, or if more than one, the trial locations; and who is, if the trial is conducted by a team of health care professionals at that location or locations, the leader responsible for that team.

A health care professional is defined as:

a) a doctor

b) a dentist

(c)  a registered nurse as defined in regulation 8(1) of the Human Medicines Regulations 2012 (“the 2012 Regulations”)

(d)  a pharmacist

(e)  a person registered in the register of optometrists maintained under section 7(a) of the Opticians Act 1989

(f)  a person registered in the Health and Care Professions Council register (as defined in regulation 8(1) of the 2012 Regulations) as a member of a relevant profession within the meaning of article 2 of, and paragraph 1 of Schedule 3 to, the Health Professions Order 2001 other than a social worker registered in Part 16

(g)  a registered osteopath as defined by section 41 of the Osteopaths Act 1993

(h)  a registered chiropractor as defined by section 43 of the Chiropractors Act 1994

(i) a person registered under the Anaesthesia Associates and Physician Associates Order 2024

(j) a registered midwife as defined in regulation 8(1) of the 2012 Regulations

A ‘chief investigator’ in relation to a clinical trial conducted at a single trial location is the investigator for that location, or in relation to a clinical trial conducted at more than one trial location, the health care professional, whether or not that health care professional is an investigator at any particular location, who takes primary responsibility for the conduct of the trial.

Reference is made to ICH E6(R3) with regards to expectations on the qualification and training of investigators and full investigator responsibilities.

Sponsors should also note that a qualified physician (or, where appropriate, a qualified dentist) who is an investigator for the trial should have the overall responsibility for trial-related medical care and decisions on behalf of participants. Therefore, where a trial includes investigators meeting criteria c-j above, a doctor or dentist (as appropriate) should also be included as a member of the trial team and be delegated medical oversight for the trial. 

Adverse event (AE)’: An ‘adverse event’ is defined as per regulation 2(1) of the Clinical Trials Regulations as follows: Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.

An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with any intervention conducted due to the participant participation in the clinical trial, even if not associated to a medicinal product, should also be considered as an AE.

Adverse reaction (AR): An ‘adverse reaction’ is defined in regulation 2(1) of the Clinical Trials Regulations as follows: any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant.

The definition implies a reasonable possibility of a causal relationship between the event and the IMP. This means that there are facts (evidence) or arguments to suggest a causal relationship.

An untoward and unintended response to a non-IMP should be recorded as an AR. (see also Reporting adverse events and serious adverse events.

The definition covers also medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of the product.

Serious adverse event (SAE), serious adverse reaction (SAR) or unexpected serious adverse reaction (SUSAR): A serious adverse event, serious adverse reaction or unexpected serious adverse reaction is defined in regulation 2(1) of the Clinical Trials Regulations as any adverse event, adverse reaction or unexpected adverse reaction, respectively, that–

(a)  results in death,

(b)  is life-threatening,

(c)  requires hospitalisation or prolongation of existing hospitalisation,

(d)  results in persistent or significant disability or incapacity, or

(e)  consists of a congenital anomaly or birth defect.

These characteristics/consequences have to be considered at the time of the event. For example, regarding a life-threatening event, this refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

Medical and scientific judgement should be exercised in deciding whether an event is ‘serious’ in accordance with these criteria.

SAEs include all serious events independent of whether they have a suspected causal relationship to the investigational medicinal product (IMP) or not.

Some medical events may jeopardise the participant or may require an intervention to prevent one of the above characteristics/consequences. Such events (also referred to as ‘important medical events’) should also be considered as ‘serious’ in accordance with the definition.

In general, hospitalisation means that the participant has been admitted to the hospital for inpatient care, for example to an inpatient ward or to an emergency department for observation and/or treatment (usually involving at least an overnight stay), that would not have been appropriate in the physician’s office or outpatient setting. The protocol should clarify what is considered as hospitalisation in the context of the trial setting since this may vary depending on the overall risk assessment for the trial. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered serious. Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is generally not considered an SAE.

‘Serious’ and ‘severe’ are not synonymous. Severity refers to the intensity of the event/reaction and is often classified by its effect on the everyday living of the participant as mild, moderate or severe. Seriousness refers to the outcome or action criteria of an AE or AR and serves as a guide for defining regulatory reporting. For example, a headache may be severe (prevents everyday activities) but is not considered serious (does not require inpatient hospitalisation, nor results in persistent disability/incapacity/congenital anomaly/birth defect and is neither life- threatening nor results in death).

Unexpected adverse reaction: An ‘unexpected adverse reaction’ is defined in regulation 2(1) of the Clinical Trial Regulations as follows: an adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in either (a) or (b) below.

(a)   in the case of a product with a marketing authorization, in the summary of product characteristics (SmPC), or equivalent document, for that product.

(b)  in the case of any other investigational medicinal product, in the investigator’s brochure relating to the trial in question.

Reports which add significant information on the specificity, increase of occurrence, or severity of a known, already documented serious adverse reaction constitute unexpected events.

For serious adverse reactions and determination of expectedness the version of the RSI at the moment of occurrence of the event applies, not the RSI at the time of case receipt by the sponsor. See Reference Safety Information (RSI).

Notifiable clinical trials

Safety recording and reporting for notifiable trials must follow all requirements as outlined in this current guideline.

MedDRA coding

Investigators should record the verbatim term for any AE/SAE in a participant. However they should also make every effort to include the relevant preferred term (PT), particularly where a PT is easily matched to the verbatim term.

MedDRA coding should be performed as per the MedDRA ‘Best practice guidelines and Points to Consider’ document which requires selection of the lowest level term and then review to determine the MedDRA PT which an event codes to. When recording and reporting safety data MedDRA should be used for consistency across the trial and with the RSI.  Any risk-proportionate and justified adaptions to coding expectations should be written in the protocol and justified, for example, if the sponsor is not coding AEs, SAEs and only coding SARs. 

Terms for SUSAR reporting and DSURs

For reporting SUSARs to the MHRA and for a DSUR, the latest version of MedDRA should be used and terms coded to the PT level. The coding facilitates the presentation and comparison of the safety data. The System Organ Class (SOC) alone should not be used to determine SUSAR reporting as this would be at too high a level and not specific enough to ensure the assessment can be made against the PTs specified in the RSI. If the investigator has included a term that does not directly match to a MedDRA PT then both the MedDRA PT and the verbatim term should be included in the SUSAR report.

Reporting adverse events (AEs) and serious adverse events (SAEs)

The investigator’s responsibilities include:

• reporting of serious adverse events to the sponsor
• reporting of certain non-serious adverse events and/or laboratory abnormalities to the sponsor

The investigator must report all serious adverse events immediately to the sponsor except for those that the protocol or investigator’s brochure identifies as not requiring immediate reporting. The immediate report shall be followed by detailed, written reports. The purpose of this obligation is to ensure that the sponsor has the necessary information to continuously assess the benefit-risk balance of the clinical trial. Therefore, the immediate report should be made by the investigator within a very short period of time and under no circumstances should this exceed 24 hours following knowledge of the serious adverse event. The follow-up report should allow the sponsor to determine whether the serious adverse event requires a reassessment of the benefit-risk balance of the clinical trial, if the relevant information was not already available and provided in the initial report.

In cases where reporting is not required immediately the investigator should report within the appropriate time frame, taking account of the specificities of the trial and of the serious adverse event, as well as possible guidance in the protocol or the investigators brochure (IB).

The investigator does not need to actively monitor participants for adverse events once the trial has ended, unless provided otherwise in the protocol. Serious adverse events considered related to the IMP (i.e. SARs) occurring to a participant after the treatment of that participant has ended should be reported to the sponsor if the investigator becomes aware of them.

Clinically significant abnormal laboratory findings are considered AEs, however abnormal laboratory findings may not be considered as AEs if there is no change compared to baseline values. Certain abnormal laboratory parameters should also be specified in the protocol as requiring reporting within the same timeframes as SAEs, depending on the IMP safety profile. These must be clearly stated in the protocol and made clear to the concerned laboratory to ensure that these ‘alert values’ are reported immediately to the investigator for onward reporting to the sponsor.

The sponsor’s responsibilities entail:

• recording of adverse events which are reported to him by the investigator(s)
• reporting of suspected unexpected serious adverse reactions (‘SUSARs’) to the licensing authority
• annual safety reporting to the licensing authority

The sponsor should continuously weigh anticipated benefits and risks of the clinical trial, which includes ongoing safety evaluation of IMPs. Sponsors are encouraged to provide a risk mitigation table in the IB (or other supporting document) which outlines the predicted risks related to the IMP(s), based on both non-clinical and clinical data, as well as other trial related risks (for example, procedure related risks), together with the mitigation steps put in place for each risk.

Example of a risk table

Potential Risk	Summary of Data/Rationale for Risk	Mitigation
Risks related to non-clinical data
(GI events)	(non-clinical summary of risk)	(summary of mitigation such as eligibility criteria, safety monitoring, toxicity management, discontinuation criteria)
Risks related to clinical data
(Hypotension)	(class effect seen with other products)	(summary of mitigation such as eligibility criteria, safety monitoring, toxicity management, discontinuation criteria)

There is no mandatory requirement for the sponsor to inform the Ethics Committee or investigators of SUSARs. However, to comply with ICH E6(R3) notification of safety information to investigators (which includes SUSARs) may be appropriate and actioned if required. The sponsor may wish to notify investigators of the occurrence through a Dear Investigator letter or an updated Investigator’s Brochure (IB). Where urgent action is required as a result of a SUSAR, the sponsor should also consider whether an Urgent Safety Measure is required.

The sponsor should arrange for systems and written standard operating procedures to ensure compliance with the necessary quality standards at every stage of case documentation, data collection, validation, evaluation, archiving, reporting and following-up.

Delegation of tasks does not remove the ultimate responsibility of the sponsor or investigator for the conduct of the clinical trial in accordance with the applicable legislation.

AEs, including SAEs, should be recorded by the sponsor and the investigator from the signature of informed consent to the end of the trial unless otherwise provided for in the protocol. For example, where obtaining consent is delayed due to the nature of the trial (such as those in emergency medicine scenarios), safety reporting should commence from the enrolment of the participant, which should be explicitly defined in the protocol.

Adverse events (including laboratory abnormalities) identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified in the protocol.

Assessment of seriousness, causality and expectedness

The sponsor is responsible for ensuring that all adverse events are reported which, cumulatively:

• have a reasonable possibility of a causal relationship to an IMP
• are serious and
• are unexpected

Seriousness

The judgement as to whether the event is serious is usually made by the reporting investigator.

Causality

The assessment of whether there is a reasonable possibility of a causal relationship is usually made by the investigator. Where the investigator is not a doctor or dentist, causality assessment should be evaluated with respect to the usual remit of the investigator. For example, if a nurse prescriber evaluates causality as part of their regular duties, then it may be appropriate to have them evaluate causality in the trial. However, where causality assessment is not part of their regular duties, or if the nature of the IMP means other safety considerations may need to be considered, then causality should be delegated to the doctor or dentist member of the team, as they have responsibility for medical oversight.

In accordance with ICH-E2A, the definition of an AR implies at least a reasonable possibility of a causal relationship between a medicinal product and an AE. An AR, in contrast to an AE, is characterised by the fact that a causal relationship between a medicinal product and an occurrence is suspected. Thus, in a clinical trial setting, a causal relationship to the IMP is either considered to be suspected or not for each individual AE which occurs.

Numerous methods of causality assessment of ARs have been and are currently used worldwide. Therefore, the ISO ICSR standard allows the possibility to provide several results of causality assessment by using one or more methods of assessment. However, in all cases classification of an AE except “not related” should be considered that there is a possible causal relationship with the IMP. If an investigator uses the WHO classification of causality, ‘unlikely’ and ‘not’ are considered to be not related.

In case of ARs assessed as ‘unknown’ or ‘not assessed’ for which the investigator cannot make a decision with regard to relatedness to the IMP the sponsor should consult the reporting investigator and encourage him/her to express an opinion.

The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, the opinion of both the investigator and the sponsor should be provided with the report. If (despite all efforts) the causality assessment cannot be made by the investigator SAEs should be considered to be related to the IMP and reported as SUSARs if they are not listed as an expected SAR in the RSI. In general, SAEs with “unknown causality” or “causality not assessed” will not be accepted to support the inclusion of expected SARs in RSI. Please see the section of this guidance on RSI.

Expectedness

Assessment of expectedness is usually done by the sponsor. The expectedness of a serious adverse reaction is assessed in the light of the RSI. If information on expectedness has been made available by the reporting investigator, this should be taken into consideration by the sponsor. However, it should be noted that including expectedness on an SAE form is not required if investigators have not specifically been delegated to perform this function.

SAEs that are not related to the IMP, i.e. are not SARs, do not need an expectedness assessment against the RSI to assess whether they meet the criteria for a SUSAR. A sponsor should therefore evaluate the need for including expectedness on the SAE form given this is not required for SAEs and given the point above that expectedness is usually a sponsor responsibility.

If expectedness has been delegated to investigators, then they should have the location of the RSI clearly identified to them to ensure correct evaluation. It should also be clear that the RSI has been authorised by the licensing authority, either as part of the initial application or via a subsequent substantial modification. The current version of the RSI document must be specifically distributed, particularly if the RSI is in an SmPC. It is not acceptable to direct an investigator to a website where multiple versions are available or where a more recent but unauthorised version is available.

Reporting for advanced therapy medicinal products (ATMPs)

Specific considerations should be taken for advanced therapy medicinal products, for example with regards to length of follow-up and recording and reporting of safety events beyond the general requirements in this guidance. There may also need to be specific consideration for additional reporting of events defined in the protocol as requiring expedited reporting in line with an SAE, even if the event does not meet the definition of serious. Such examples include events related to administration or trial procedures, related to the nature of the IMP (such as cytokine release syndrome) or other events as identified in a risk analysis.

Particular notes should be taken by the sponsor to address potential long-term effects and how these will be collected, recorded and (if required) reported. This includes consideration for recording throughout the duration of the trial as well as evaluation of whether longer-term evaluation is appropriate, for example via a registry.

Reporting of pregnancies, medication errors and misuse/abuse of IMPs

All reports of exposure during pregnancy, medication errors, misuse or abuse in relation to the IMP should be recorded by the investigator and notified to the sponsor. General rules in this guidance document apply to these events as regards the expedited reporting of SUSARs, the submission of the DSUR and the implementation of risk mitigation measures.

Pregnancy does not meet the definition of an SAE. A congenital anomaly or birth defect is, however, considered an SAE. When a pregnancy occurs in a trial, either in a female participant or the female partner of a male participant, this should be followed up until at least the end of the pregnancy. It is recommended that pregnancy cases are followed up initially as soon as the sponsor is notified and then tracked in order to be able to request further follow-up near term, to allow collection of information on the pregnancy outcome. Without follow-up of the pregnancy, it would not be possible for the trial team to know if a congenital anomaly or birth defect occurred, and therefore if there was an SAE that must be included in the safety evaluation of the IMP. A process should also be in place for following pregnancy outcome data in the event the end of trial has been declared but some outcome data is still pending. Follow-up is dependent on obtaining informed consent for this from the participant (or their partner in the case of male trial participants). It may not be necessary for all trials to collect information on pregnant partners of male participants; however, if there is a known or suspected effect on spermatogenesis or if there is potential for the IMP to be transferred to the foetus in the seminal fluid, follow-up would be necessary. This should therefore be discussed in the protocol (and risk assessment) and also included in the trial consent form.

Reporting safety for non-IMPs

In case of a suspected interaction of a non-IMP with the IMP the reporting rules for the IMP apply.

Safety reporting (referring to all adverse reactions) with regard to authorised non-IMPS should be made in accordance with post-marketing requirements for that non-IMP, irrespective if they are used in accordance with the terms of the marketing authorisations of these products. It should be noted that investigators and sponsors are encouraged to report suspected adverse reactions to the non-IMP to MHRA (via the Yellow Card Scheme) or to the marketing authorisation holder.

Safety of non-authorised non-IMPs (that should be used only exceptionally in clinical trials) should be reported in the same way as IMPs. Accordingly, SARs related to non-authorised non-IMPs should all be considered as SUSARs and should be reported to the licensing authority. If any adverse reaction associated with the non-IMP is likely to affect the safety of the trial subjects, the sponsor should take any appropriate actions, including an urgent safety measure, as applicable.

Sponsors are reminded that where an adverse event occurs that, following a causality assessment, is suspected to be related to a NIMP only, the requirements per regulation 32 of the Clinical Trials Regulations still apply.

Reference safety information (RSI)

The Reference Safety Information (RSI) is used for the assessment of the expectedness of all ‘suspected’ SARs that occur in clinical trials. Therefore, the content of the RSI should be a list of expected SARs and their frequencies. The SARs are classified using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). These ‘expected SARs’ should be restricted to ‘suspected’ SARs that were previously observed more than once, where, after a thorough assessment by the sponsor, reasonable evidence of a causal relationship between the event and the IMP exists. This confirmation should be based, for example, on the comparative incidence with other ‘suspected’ SARs in all previous and ongoing clinical trials and on a thorough evaluation of causality of the individual reported case. This should be done from the perspective of events previously observed, not on the basis of what might be anticipated from the pharmacological properties of the IMP.

Frequency of events

Suspected SARs that have occurred once are not usually qualified to be included into the RSI, unless there is a very strong plausibility of a causal relationship with the IMP and a robust justification based on medical judgement is provided. A robust rationale is a medical rationale which cannot only be the biological plausibility based on the mechanism of action of the IMP and the presence of risk-mitigation strategies. Importantly, the occurrence of a ‘suspected’ SAR more than once is not per se an adequate justification for the addition of the term to the RSI as an expected SAR. A thorough assessment by the sponsor is also required for ‘suspected’ SARs that have occurred more than once, and justification for the addition to the RSI should be submitted alongside the proposed addition. Explicit justification should be provided when ‘suspected’ SARs are included in the RSI with an unknown frequency on the basis of post-marketing experience. It might be acceptable that “suspected” SARs based on the post- marketing experience are added in the RSI only for the same indications or relevant indications (the same therapeutic areas and same expositions). However, if the indications of post-marketing experience are different of the clinical trial, the RSI should be based only on the clinical experience in the relevant indication. Thus, separate RSIs might be needed within one IB for an IMP for different indications.

Fatal and life-threatening events

As a general rule, sponsors should not expect an IMP to cause fatal SARs. Thus, fatal SARs should usually be considered unexpected even if previous fatal SARs have occurred.

If there are expected life-threatening or fatal SARs listed in the RSI section of an IB, the RSI should include the number of suspected life-threatening and fatal suspected SARs that have occurred. These data should be provided in separate columns.

The numbers of all other life-threatening or fatal ‘suspected’ SARs that have previously occurred but that are considered unexpected should not be listed in the RSI and should be listed elsewhere in the IB. It is recommended to provide this information either in a subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’.

Fatal SARs can only be considered expected for IMPs with a marketing authorisation (MA) when it is clearly stated in the table or list of ARs in section 4.8 of Summary of Product Characteristics (SmPC) that the IMP can cause these fatal SARs, and where that SmPC is submitted as the RSI for the trial.

If a fatal and/or a life-threatening SAR is added to the RSI section of an IB, an update to the benefit/risk statement for clinical trial subjects should be provided and adequate risk minimisation measures should be proposed in an updated clinical trial protocol.

Location of the RSI

An RSI is required for each IMP in a clinical trial, including the IMP under direct evaluation and comparator IMPs. An application may therefore include more than one document which include the RSI, one for each IMP.

The RSI should be provided as follows.

In the case of a product with a marketing authorisation

The RSI is located in the summary of product characteristics (SmPC) or equivalent document, for that product.

• For an IMP with a MA in the UK/GB or EU, which is used according to the MA, the RSI should be section 4.8. ‘Undesirable Effects’ of the appropriate SmPC. If more than one MA is in place with different SmPCs, the sponsor should select the most appropriate SmPC as the RSI, with reference to participant safety, and justify its selection. A UK/GB or EU SmPC should be submitted, but if it does not fit the trial, an SmPC (or equivalent, such as US prescribing information (USPI)) from other ICH countries may be submitted. If an SmPC is used as the RSI, the study protocol should be compliant with the risk mitigation measures included in the SmPC. The SmPC should be submitted as a separate document i.e., Section 4.8 of the SmPC should not be copied into the RSI of an IB or into the protocol. Note that whereas section 4.8 of the SmPC aims at giving an exhaustive picture of the safety profile of a medicinal product, the purpose of the RSI is to provide clarity to all stakeholders of which SARs are unexpected and therefore qualify for expedited reporting.
• Ideally the latest available version of an SmPC should be the version submitted in any application unless otherwise justified.
• If it is proposed to use an IMP outside the indication of MA within the trial, section 4.8 of the SmPC for the IMP(s) could be used as the RSI, if scientifically justified by the sponsor in the clinical trial application cover letter. If a scientific justification cannot be provided then the RSI should always be a clearly separated specific section within the IB, and not an SmPC.
• The version of an SmPC submitted at the time of an initial application and subsequently authorised is the version of the RSI that must be used unless later updated via a substantial modification. For example, if a sponsor submits SmPC version 2.0 dated 01/01/2022 with the initial application then that is the version of the SmPC that must be used as the RSI.
• In the scenario where an IMP has an MA but the marketing authorisation holder also has an IB available for that IMP then either document can be used as the RSI, but must be justified. Once either an SmPC or IB has been selected as containing the RSI to be used for the trial then only that document must be included in applications and updates must only be provided using the same document type.

In the case of any other investigational medicinal product

The RSI of any other IMP should always be a clearly separated specific section within the Investigator’s Brochure.

• The RSI section within the IB should be a clearly-identified section titled “Reference safety information“ which may either be integrated into the section of the IB with the ‘Summary of Data and Guidance for the investigator’ or be a new section. When the RSI is contained within an IB, the sponsor should clearly indicate that the RSI section outlines expected SARs for regulatory reporting purposes and that the information within the RSI section does not present a comprehensive overview of the safety profile of the IMP.
• If the RSI is within the IB for an IMP and there is not yet a clearly identified section to this effect, where all expected SARs are included in form of a table, the clinical trial application (initial or substantial modification) risks being rejected.
• There may be situations where the IMP is not expected to cause any SARs, e.g. early in the clinical development of an IMP when participant exposure is low. In these cases, a clearly defined section of the IB called ‘RSI’ should still be present and if there are no ‘expected SARs’ for the IMP at the point of submission then the RSI section must clearly state this. See example below.

Example of RSI with no expected events

‘No SARs are considered expected by the sponsor for the purpose of expedited reporting of SUSARs and identification of SUSARs in the “Cumulative summary tabulation of serious adverse reactions” in the DSUR for the IMP.’

The Company Core Data Sheet (CCDS) is not accepted as the RSI by itself. However, the CCDS may be contained in an appendix to the IB and include the RSI as a separate clearly identified section titled, e.g., “Reference safety information for assessment of expectedness of serious adverse reactions”. In that case, the RSI section must be compliant with the guidance of this document.

The location of the RSI for each IMP should always be clearly indicated in the cover letter of the trial application (initial or substantial modification).

RSI format

The RSI should be presented in the form of a table, where the nature of the ‘expected SARs’ must be listed by MedDRA body System Organ Class (SOC) and Preferred Terms (PTs; lower level terms within the PTs will also be considered expected) followed by the frequency. The latest MedDRA version should always be used. The frequency must be calculated on an aggregated level and should be based on the previously observed SAEs considered related to the IMP by the investigator or analysed by the sponsor as SAR or SUSAR (events upgraded by sponsor).

The frequency numbers are preferred to be in categories similar to the SmPC, section 4.8, thus indicated using Council for International Organizations of Medical Sciences (CIOMS) categories. The categories are: very common, common, uncommon, rare and very rare. A frequency of ‘not known’ is not deemed acceptable because it does not allow assessment of whether the new SAR report represents an increased frequency and therefore is unexpected. When there is an insufficient number of participants exposed to the IMP to use these categories or low numbers (e.g., two) of the expected SARs observed, the numbers of each ‘expected SAR’ should be provided, together with the number of patients exposed (refer to example below).

Inclusion of events seen in a post-marketing setting is acceptable. However, when such events are included it must be clear that only those previously seen as serious are included. A frequency of “unknown” is not allowed. It is acknowledged that the true frequency category may not be known, therefore, absolute numbers for each event should be provided. Alternatively, it is acceptable to provide a frequency category that has been calculated as per the “Adverse reactions from spontaneous reporting” guidance as used for an SmPC.

Example of an RSI table: Serious Adverse Reactions for the IMP considered expected for safety reporting purposes. (n=number of participants who have experienced the SAR)

		Number of participants exposed (n=328)	Number of participants exposed (n=328)	Number of participants exposed (n=328)
SOC	SARs	All SARs n(%)	Occurrence of fatal SARs1 n(%)	Occurrence of life-threatening SARs1 n(%)
Gastro-intestinal disorders	Intestinal perforation	9 (2.7)	3 (0.9)	6 (1.8)
Hepatobiliary disorders	ALT increase	12 (3.6)	Not applicable	Not applicable
Hepatobiliary disorders	AST increase	9 (2.7)	Not applicable	Not applicable
Cardiovascular disorders	Myocarditis	33 (10.0)	Not applicable	2 (0.6)
Cardiovascular disorders	Bradycardia2	(rare)	Not applicable	Not applicable

^{1.If in exceptional cases individual fatal and life-threatening SARs are considered expected for an IMP, the respective columns should always be included in the table. For the rest of the SARs (rows) where fatal/life-threatening outcomes are not expected, this can be stated as “not applicable” with a footnote clarifying that information on numbers for unexpected fatal/life-threatening SARs can be found elsewhere in the IB. If no fatal/life-threatening SARs are expected at all for the IMP this must be clearly stated in the RSI, reference needs to be made to other IB sections and the respective columns can be omitted.}

^{2.Example footnote: ‘Bradycardia seen in post-marketing setting only, not in clinical trials. Frequency calculated as per SmPC guidance: event not seen in 328 participants exposed in clinical trials. Post-marketing events were serious and occurred more than once. Rare: occurrence ≥ 1/10 000 but < 1/1000’.}

If the IMP is under development in different medical conditions or for different populations (e.g., adults and minors), separate tables of expected SARs by indication or population should be provided if the expected SARs are different e.g. for oncology conditions, non-oncology diseases and for paediatric trials. It may also be appropriate to include fewer expected SARs in the RSI for minors in comparison to the RSI that has been used for the investigation in adults describing only the serious ARs expected for the paediatric population on the basis of the available experience in the paediatric population. Regarding young children (especially for children <12 years old), the RSI should only be based on the experience in the paediatric population and the sponsor may not assume a paediatric safety profile similar to that of adults until paediatric development is complete.

Terms in the RSI

The use of medical concepts or unspecific terms in the RSI of an IB, e.g. “Infections” or “Arrhythmia” is not acceptable. Only MedDRA PTs e.g. exfoliative dermatitis, urticarial rash or hives, herpes zoster, pneumonia, sepsis, atrial fibrillation are allowed.

If there are multiple lower level terms (LLTs) within a single PT, they are all expected (for example if the PT ‘pyrexia’ is included in the RSI table, then the LLT ‘fever’ is also considered expected). A product that is known to cause immunosuppression may also lead to infections, however, only the PTs of the type of infections that have been observed should be considered expected, i.e. all infections cannot be considered expected. A ‘suspected’ SAR should be considered unexpected unless the PT is listed as an expected SAR in the RSI. General PT such as respiratory infection should not be listed in the RSI, but a more specific term such as pneumonia should be listed instead..

A provision of severity grades using Common Terminology Criteria for Adverse Events (CTCAE) grading system in the RSI is not required. However, reports which present significant information on specificity or severity of a known, already documented SAR represent unexpected events (refer to table for examples).

Example of SUSARs and reasons for their reporting

Listed SAR in RSI	‘Suspected’ SAR in individual Case Reports	Unexpected due to specificity or severity
Acute renal failure	Interstitial nephritis	Specificity
Hepatitis	Fulminant hepatitis	Severity
Cerebral vascular accident	Cerebral thromboembolism	Specificity
Exfoliative dermatitis	Stevens-Johnson Syndrome	Severity and Specificity
Transient increase in liver function tests	Increased liver function tests persisting for several months	Severity
Hypertension	Hypertensive crisis	Severity
Herpes Zoster	Multi-dermal herpes zoster	Severity
Sepsis	Septic shock	Severity
Supraventricular Cardiac Arrhythmia	Atrial fibrillation	Specificity

In addition, if the frequency of the suspected SAR is higher than stated in the RSI (higher frequency may be observed as a result of sponsor’s analyses), the SAR should be considered a SUSAR and the narrative should include a discussion of the changes. This is applicable for all trials and especially after early phase of development when there are sufficient data available for analysis.

Reports which provide additional information on the specificity of an expected SAR should also be considered unexpected.

Synonymous medical terms (e.g. somnolence, drowsiness) are those representing truly the same medical phenomenon. If one of the synonymous medical terms is included in the RSI, it will cover also the other synonymous terms in the RSI. This is not to be confused with different forms of the same medical phenomenon e.g. different forms of rash such as rash maculo-papular, rash papular, rash pustular, etc., which are not considered to be the same medical phenomenon and for which specific PTs in the RSI have to be listed.

Examples of synonymous medical terms

Listed PTs for expected SARs in RSI	‘Suspected’ SARS in Synonymous medical terms
Pneumonia	Right upper lobe pneumonia
Gastrointestinal bleeding	Melaena
Hypophosphataemia	Blood phosphorus decreased

The following safety information should not be included in the RSI section of an IB, but should be presented elsewhere in the IB, e.g. in a table, preferably located in the subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’:

• Events seen only in non-clinical studies
• AEs that were considered unrelated to the IMP by both the investigator and the sponsor,
• SAEs and non-serious AEs that were considered unrelated to the IMP by both the investigator and the sponsor
• Non-serious ARs
• All SARs that are not considered expected
• SARs that have occurred only once, unless there is a very strong plausibility of a causal relationship with the IMP and a robust justification based on medical judgement is provided.
• Deaths or SAEs also considered efficacy endpoints in trials with high mortality or morbidity accepted in the authorised protocol by the competent authority to be treated as disease related events and not participant to systematic unblinding. However, careful assessment should be performed in cases where disease related events appear to be enhanced by the IMP.
• SARs that are expected for similar products within the therapeutic class, which did not occur in participants taking the IMP.

Updating the RSI

It is highly recommended to update the RSI section of the IB once a year in alignment with the annual reporting period for a [DSUR] and the requirement as per regulation 3A of the Clinical Trials Regulations to validate and update the IB annually. It is expected that cumulative safety data are reviewed during the preparation of an DSUR and used to support the RSI update. If the RSI is located in an SmPC then periodic review for updates (at minimum annually), using a risk-based approach, is expected.

If a SAR is added to the RSI section of an IB, an update of the benefit/risk statement for clinical trial participants should be provided and adequate risk minimisation measures should be proposed in the updated clinical trial protocol(s). This is especially relevant if it is a fatal case where the IMP has a marketing authorisation.

When to update the RSI

It is best practice to submit an updated version of the IB (as a substantial modification application) and a new DSUR in parallel, or alternatively to submit the application of substantial modification for the authorisation of the updated RSI within one month after the submission of the new DSUR at the latest. The new RSI in the updated IB can only be used for the assessment of expectedness of ‘suspected’ SARs for the purposes of expedited reporting of SUSARs in a specific trial after authorisation of the substantial modification on the aspects regarding the RSI. Thus, the expectedness of any suspected SAR that occurred before the new RSI is authorised, should be assessed according to the authorised version of the RSI at that time.

For the purposes of the identification of SUSARs in the ‘Cumulative summary tabulation of serious adverse reactions’ in a DSUR, Sponsors should use the ‘RSI in effect ‘at the start’ of the annual reporting period. The “RSI in effect at the start of the annual reporting period” should be the version of the RSI in the IB approved in the UK at a timepoint closest to the data lock point at the start of the DSUR reporting period. This may include an IB version approved after the data lock point, within a period of approximately 3 months (see Figure 1: Diagram explaining which reference safety information (RSI) should be used in the Development Safety Update Report (DSUR)).

The RSI used to identify SUSARs in the DSUR should be submitted with the DSUR, as well as the proposed new RSI, and any changes to the RSI should be detailed in the ‘Changes to the Reference Safety Information’ section of the DSUR. Note that if the IB has been updated and there are no proposed changes to the RSI, the new IB should still be submitted with the DSUR.

Substantial modifications

Updates to the RSI (including to section 4.8 of an SmPC, when it is used as the RSI) are generally considered to be substantial modifications. If the change to the RSI involves an increase in frequencies with no new expected adverse reactions or if the change is an update to section 4.8 of the SmPC, the modification should be submitted as a Route B substantial modification. Other updates to the content of the RSI should be considered Route A substantial modifications (however, changes to the format of the RSI that do not involve a change in the content may be considered a minor modification). For further guidance on Route A and Route B substantial modifications, refer to the guidance on Modifying a clinical trial approval.

When submitting a substantial modification that involves an IB or SmPC update, the cover letter should indicate if the RSI is being updated or not. Upon submission of an IB in a substantial modification application containing an update to the RSI, which is not accompanied by a protocol modification, the sponsor should specify in the submission cover letter what risk mitigation measures are already in place in the protocol to manage any new safety issues and if these new safety issues are adequately covered in the participant information leaflet (informed consent form) or if it needs to be updated. References to any parallel DSUR submission should also be given in the cover letter. A tracked changes version of the IB should be provided. In cases where justifications for modifications to the RSI are provided in additional documents, these documents should be submitted simultaneously.

It is strongly recommended to submit a substantial modification application that includes an updated RSI to all clinical trials which refer to the same RSI at the same time including information in the cover letter about all ongoing CTs to which the substantial modification would apply and for which an application has been or will be submitted.

An urgent update to the safety data in the IB may be deemed necessary by the sponsor or regulatory authorities at any time during the conduct of a clinical trial. This information can be added to other sections of the IB (preferably to the Safety and Efficacy section under Effects in Humans and/or Summary of Data and Guidance for Investigators section) with appropriate submission as a substantial modification if relevant. However, the RSI section of the IB should only be updated following the analyses of SUSARs for a DSUR and should not be updated multiple times during a reporting period.

Figure 1: Diagram explaining which reference safety information (RSI) should be used in the Development Safety Update Report (DSUR).

A sponsor is at the start of their reporting period for DSUR #10 and maps out subsequent RSI, IB and DSUR requirements.

• At the data lock point (DLP) IB version 5 is in place.
• IB v6 is prepared and finalised, including an updated RSI.
• DSUR #9 is prepared and submitted within 60 days of the DLP.
  • The DSUR includes IB v6 as an appendix, but is not yet distributed or used for expedited reporting as it has not been approved by the licensing authority.
• In parallel, IB v6 is submitted as a substantial modification.
• A SAR occurs at this timepoint, and is deemed unexpected according to the RSI in IB v5, so is reported as a SUSAR.
• IB v6 is approved and the sponsor updates safety reporting procedures to utilise the new RSI from the time of approval.
• The sponsor notes that as IB v6 is the most recently approved IB since the start of the reporting period this will be the RSI for DSUR #10.
• The DLP is reached at the end of the reporting year and DSUR #10 is prepared.
  • All SARs from the time of the previous DLP to the time of the approval of IB v6 are reviewed for expectedness against the RSI in IB v6. The earlier event deemed a SUSAR using IB v5 is not considered a SUSAR using IB v6. The DSUR includes the event as an SAR but not a SUSAR.
• IB v7 is prepared and submitted as a substantial modification in parallel with DSUR #10, and the cycle restarts.

Figure 2: Diagram explaining which reference safety information (RSI) should be used in the Development Safety Update Report (DSUR) where the RSI has been updated during the reporting period

• At the data lock point (DLP) IB version 5 is in place.
• IB v6 is prepared and finalised, including an updated RSI.
• DSUR #9 is prepared and submitted within 60 days of the DLP.
  • The DSUR includes IB v6 as an appendix, but is not yet distributed or used for expedited reporting as it has not been approved.
• In parallel, IB v6 is submitted as a substantial modification.
• A SAR occurs at this timepoint, and is deemed unexpected according to the RSI in IB v5, so is reported as a SUSAR.
• IB v6 is approved and the sponsor updates safety reporting procedures to utilise the new RSI from the time of approval.
• The sponsor notes that as IB v6 is the most recently approved IB since the start of the reporting period this will be the RSI for DSUR #10.
• In the middle of the reporting year the sponsor considers new clinical data warrants an update to the IB that is deemed substantial as well as substantial updates to several trial protocols. At the same time, the RSI is reviewed and the new data are considered by the sponsor to support adding new terms to the RSI. The benefit/risk section of the IB is also updated. A substantial modification for IB v6 to IB v7 is submitted and approved. The sponsor updates safety reporting procedures to utilise the new RSI from the time of approval.
• Further SARs occur, some of which are deemed SUSARs according to the RSI in IB v7.
• The DLP is reached at the end of the reporting year and DSUR #10 is prepared.
  • All SARs from the time of the previous DLP to the time of the approval of IB v6 are reviewed for expectedness against the RSI in IB v6. The earlier event deemed a SUSAR using IB v5 is not considered a SUSAR using IB v6.
  • In addition, all SARs that occurred from the implementation of IB v7 to the DLP are reviewed for expectedness against the RSI in IB v6. A few SARs remain as SUSARs as they are unexpected in both IB versions, and these are listed in DSUR #10 as such. Many of the SARs, however, were considered expected according to IB v7 but are now unexpected (are now SUSARs) according to IB v6. They are not subject to expedited reporting as they were reviewed according to the RSI in place at the time the events occurred. However, the sponsor includes them in DSUR #10 as SUSARs.
  • DSUR #10 includes a discussion of the justification to update the RSI in the middle of the reporting period. The licensing authority requests further information as the rationale is based on a limited clinical dataset, the update is not supported by the current DSUR and the sponsor has omitted a discussion of the new expected events in terms of signal management. The sponsor is also reminded that updating the RSI in the middle of a reporting period is not recommended.
• IB v8 is prepared and submitted as a substantial modification in parallel with DSUR #10, and the cycle restarts.

Further example scenarios

Example scenarios are outlined below.

• Example 1: A new version of the IB is issued at the same time as the DSUR for the new reporting period and there are new events listed as expected. The sponsor must submit a substantial modification application and not implement the new IB until the modification is approved. Any change in RSI is a change in risk benefit and an updated risk benefit discussion is also included in the submission. The sponsor has approved the updated RSI internally but ensures there are robust processes in place to ensure the new version is not disseminated to investigators or pharmacovigilance departments before the modification has been approved. In addition, algorithms or expected event terms in safety databases are only updated after approval.
• Example 2: A new version of the IB is issued at the same time as the DSUR for the new reporting period and there are no changes to the RSI (no new events are listed as expected and no events removed). No substantial modification is required before the sponsor uses the new IB but the sponsor clearly documents the assessment that demonstrates the RSI has not changed and therefore does not meet the requirements of a substantial modification, in the TMF. [Sponsors should  note that the usual requirements for submission of a substantial modification still apply for non-RSI related changes (see Clinical trials for medicines: applying for approval in the UK).
• Example 3: A new version of the IB is issued mid DSUR period by the sponsors global Headquarters and there are new events listed as expected as well as new safety information that impacts the protocol. An individual risk assessment is done that assesses the new version of the IB against the current version and the RSI changes are minimal or not relevant to the ongoing studies or patient populations in the UK. The sponsor therefore chooses to continue with the current RSI in the current IB version for the purposes of SUSAR reporting for the remainder of the reporting period. The sponsor documents the whole process and submits a substantial modification at the time stating that they will not implement the new RSI until the end of the current DSUR period. At the time of the next DSUR the sponsor clearly outlines how data was collected for the DSUR and demonstrates which RSI/IB was used for which trial during the reporting period.

The examples above are also applicable to an SmPC when this is the document containing the RSI.

Non-commercial sponsors

If the RSI is within an IB which is not prepared and updated by the sponsor itself (e.g. for non-commercial sponsors using a company’s IB), the (non-commercial) sponsor should have a written agreement in place with the company in which the updated authorised IB is sent to the (non-commercial) sponsor using the same IMP immediately. The (non-commercial) sponsor is also encouraged to put in place a process to check on at least an annual basis whether there are any updates to the IB.  The (non-commercial) sponsor should submit the approved IB, together with any of the necessary modifications to the protocol as a substantial modification for their own clinical trial.

Combinations of IMPs, biosimilar IMPs, and generic small molecules

In case of trials investigating a combination of IMPs, the sponsor can either use a single RSI for each IMP included in the combination, that is one RSI per an IMP (the RSIs can be located either in the IB or SmPC as appropriate) or create an RSI table for the combination under investigation based on an evaluation of ‘suspected’ SARs to the same combination of active substances in previous trials.

The sponsor should explain how the RSI has been compiled and especially in case of new combinations, new indications or new population, take a risk-based approach to including expected SARs in RSI.

For a biosimilar product, all SARs caused by an investigational biological medicinal product whose biosimilarity to the reference product has not been proved should be considered unexpected. In addition, the protocol should include measures to mitigate both the known risks associated with the originator and the new ones associated with the biosimilar (for example potential risk of reduced efficacy when compared with the originator).

If the investigational product is a potential generic and is a small molecule that will be administered via the same route as the reference product, the sponsor may provide a robust rationale why the SARs expected for the reference product should be considered expected for the potential generic before similarity is demonstrated. The rationale should be provided at the time of the clinical trial authorisation (CTA) application. Each case will be assessed on an individual basis.

Reporting suspected unexpected serious adverse reactions (SUSARs)

Legal basis

Any SUSARs that occur during a clinical trial in the UK must be reported to the licensing authority under regulations 33 and 34 of the Clinical Trials Regulations, including those that:

• are associated with comparators and placebos (where an SAE is related to placebo)
• occur at non-UK sites if there are also trial locations in the UK
• occurred during the trial but were identified after trial completion

SUSARs should also be reported if they occur in a non-UK trial of the same IMP by the same sponsor of the trial running in the UK, or if they occur in a non-UK trial of the same IMP by a sponsor that is part of the same parent company as, or is jointly developing the IMP with, the sponsor of the UK trial.

SUSARs do not have to be reported to the ethics committee or to the investigators conducting the trial, although the sponsor may wish to notify investigators of the occurrence through a Dear Investigator letter or an updated Investigator’s Brochure (IB). Please note that some changes to the IB are considered substantial modifications and must be [approved by the licensing authority and ethics committee before being implemented].

Safety recording and reporting in lower risk trials (for example those which the risk is no greater than standard of care, as evaluated in a risk assessment) can be simplified from what is described in this section, applying a risk proportionate approach. Risk adaptations to safety reporting refer to documenting of AEs in source documents, recording of AEs in the case report forms (and hence reporting to the sponsor) and to the requirements of immediate (not later than within 24 hours of obtaining knowledge of the event) reporting (of SAEs/SUSARs) by the investigator to the sponsor. Any such adaptation should be clearly stated and justified in the protocol.

Systematic failure to report SUSARs for a trial or a product(s) to the licensing authority in line with applicable regulatory requirements and guidance may be considered a serious breach.

Process for reporting SUSARs

SUSARs should be reported to the licensing authority through ICSR Submissions (for submitting single SUSARs) or the MHRA Gateway (for submitting single or bulk reports) using the E2B (R3) format.

The timelines for reporting SUSARs to the licensing authority depend on the nature of the SUSAR. The sponsor must:

• report life-threatening or fatal SUSARs within 7 calendar days beginning with the date that they became aware of it, followed by any additional relevant information within a further 8 calendar days
• report non-life-threatening or non-fatal SUSARs within 15 calendar days beginning with the date that they became aware of it
• report SUSARs specified in the protocol as not requiring immediate reporting in accordance with the reporting requirements in the protocol

The purpose of the reporting obligation is to make the licensing authority aware of SUSARs and to collect safety information on the safety profile of an IMP. This, in turn, is intended to give the licensing authority the opportunity to:

• assess, in view of the various reported SUSARs, whether an IMP poses an unknown risk to the participant, and
• take measures to protect the safety of participants, if necessary

There may be cases where a SUSAR turns out to be fatal or life-threatening, whereas initially it was considered as non-fatal or not life-threatening. The non-fatal or non-life-threatening SUSAR should be reported as soon as possible, but within 15 calendar days. The fatal or life-threatening SUSAR follow-up report should be made as soon as possible, but within a maximum of 7 days after first knowledge of the reaction being fatal or life-threatening.

In cases where a SUSAR turns out to be fatal or life-threatening, whereas initially it was considered as non-fatal or not life-threatening, while the initial report has not yet been submitted, a combined report should be created.

Medical and scientific judgement should be applied in identifying non-relevant and relevant information. In particular, new administrative information that could impact on the case management is to be considered as ‘relevant’. One example is information that may help to detect potential duplicates (e.g. new case identifiers have become known to the sponsor which may have been used in previous transmissions).

For follow-up reports, the RSI in effect and approved at the time of occurrence of the ‘suspected’ SAR should be used to assess expectedness. SUSARs should not be downgraded on the basis that the RSI was updated after the occurrence of the event.

It may transpire, after the initial reporting, that the event is not a SUSAR, for example due to lack of causality, seriousness, or expectedness (hereinafter referred to as ‘downgrade’). Downgrades should be considered as relevant information. Examples of non-relevant information are minor changes of dates or corrections of typographical errors in the previous case version.

In applying the rules on reporting of relevant information within the timelines the following should apply:

• The clock for expedited initial reporting starts as soon as the sponsor becomes aware, that is when the information containing the minimum reporting criteria has been sent to the sponsor (day zero), not when the sponsor’s staff pick up the notification. Sponsors must therefore ensure there is appropriate staffing to ensure that the 7/15-day SUSAR reporting timelines can be met. Notification by the investigator to the sponsor can be via email/fax/call/entry into the Electronic Data Capture System, etc. Where an unreported SAE has been identified through monitoring activities or other discussions with the trial team, this should also serve as day zero (i.e. when the sponsor has first become aware of an SAE).
• For fatal and life-threatening SUSARs the sponsor should report at least the minimum information as soon as possible and in any case no later than seven days after being made aware of the case
• If the initial report is incomplete, e.g. if the sponsor has not provided all the information/assessment within seven days, the sponsor is to submit a completed report based on the initial information within an additional eight days. In this instance, the receipt date should not be changed with regard to the initial report
• If significant new information on an already reported case is received by the sponsor, this information should be reported as a follow-up report within 15 days of the sponsor receiving this information.

The minimum information to be provided for an initial report of a SUSAR includes, at least, all of the following:

• valid EudraCT and/or IRAS number (where applicable)
• sponsor study number
• one identifiable coded participant
• one identifiable reporter
• one SUSAR
• one suspect IMP (including active substance name code)
• a causality assessment

In addition, in order to properly process the report electronically, the following administrative information should be provided:

• the sender’s (case) safety report unique identifier
• the receipt date of the initial information from the primary source
• the receipt date of the most recent information
• the worldwide unique case identification number
• the sender identifier

Following submission of a SUSAR the sponsor should expect to receive acknowledgement of the submission within 48 hours. If an acknowledgement is not received then the sponsor should contact the E2B support team (E2B.support@mhra.gov.uk) to determine next steps, including whether resubmission is required.

SUSARs associated with an active comparator, placebo or combination product

Comparators and placebos are IMPs. Therefore, SUSARs associated with a comparator product follow the same reporting requirements as for the test IMP.

Events associated with placebo will usually not satisfy the criteria for a SUSAR and therefore for expedited reporting. However, where SUSARs are associated with placebo (e.g. reaction due to an excipient or impurity), the sponsor should report such cases.

When the treatment of a clinical trial participant includes a combination of IMPs, the investigator should assess for every SAR if any of the IMPs could have caused it on the basis of medical judgement and without discarding causality for one IMP by only the fact that the suspected AR has been previously described for other IMP in the combination treatment. Where the causality indicated by the investigator is suspected for several IMPs, the sponsor should assess the expectedness of the SAR considering the RSIs of all suspected IMPs when separate RSIs for each IMP are used. If the AR is not expected for all suspected IMPs (according to the separate RSIs), the SAR should be considered unexpected and reported as a SUSAR. Where RSIs of the combination IMP in the IB or SmPC is used, if a suspected SAR is not present in the RSI, it should be reported as a SUSAR. A combination product SUSAR should be reported related to the combination, unless it is (in rare cases) known to which IMP the SAR is related to.

Unblinding treatment allocation

As a general rule only SUSARs on which the treatment allocation of the participant is unblinded should be reported by the sponsor to the licensing authority.

The investigator should only unblind the treatment allocation in the course of a clinical trial if this is relevant to the safety of the participant i.e. in an emergency. A separate procedure should exist for SARs unblinded for emergency purposes for the clinical management of SARs by the investigator. Failure to have in place a suitable unblinding procedure may result in a serious breach in the event a participant requires emergency treatment where the attending physician is not able to unblind their treatment allocation.

With regards to the sponsor, when an event may be a SUSAR the blind should be broken by the sponsor only for that specific participant. The sponsor must unblind the treatment for safety evaluation and regulatory reporting purposes if a SAR is unexpected as per the RSI of the IMP. The unblinding is not necessary for SARs assessed as expected for all IMPs for the purposes of expedited reporting as these would not meet the definition of a SUSAR.

Figure 3: Decision tree to determine when treatment allocation should be unblinded following a serious adverse reaction

Unblinding algorithm

The blind should be maintained for persons responsible for the ongoing conduct of the study (such as the trial management, monitors, investigators) and those responsible for data analysis and interpretation of results at the conclusion of the study. Unblinded information should only be accessible to those who need to be involved in the safety reporting or persons performing ongoing safety evaluations during the trial, for example an independent data monitoring committee.

In all cases, following unblinding, if the event turns out to be a SUSAR (for example as regards expectedness), the reporting rules for SUSARs apply.

Unblinding for combination IMPs

Combination products, that is, either a fixed dose combination (FDC) or 2 separate IMPs given simultaneously, should have a clearly defined process in the protocol for unblinding in the event of an SAR.

A FDC product is generally expected to have a single RSI and therefore any SAR should have expectedness evaluated against events listed in that RSI.

For a combination where 2 separate IMPs are given simultaneously it is usual for each IMP to have its own IB (or SmPC) and therefore the combination arm will have 2 RSIs. Any SAR should be evaluated with consideration for both RSIs. If the event is unexpected for one or both IMPs in the combination then the participant should be unblinded and a SUSAR reported appropriately.

Safety issues not falling within the definition of SUSARs – other measures

Events may occur during a clinical trial which do not fall within the definition of a SUSAR and thus are not participant to the reporting requirements for SUSARs, even though they may be relevant in terms of participant safety. Such events do not require reporting by the sponsor as SUSARs.

Examples include new events related to the conduct of a trial or the development of an IMP likely to affect the safety of participants, such as:

• SARs related to authorised non-IMPs or concomitant medication received by the participant and without interaction with the IMP. It should be noted that investigators and sponsors are encouraged to report suspected adverse reactions to the non-IMP to the licensing authority or, for authorised non-IMPs, to the marketing authorisation holder.
• SUSARs occurring in a clinical trial performed (partly or exclusively) in the UK for which he is not the sponsor. These SUSARs may come to the attention of the sponsor through individual reports, publications (such as academic literature) or regulatory authorities
• SARs occurring in a third country outside a clinical trial
• a serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial
• a significant hazard to the participant population such as lack of efficacy of an IMP used for the treatment of a life-threatening disease
• a major safety finding from a newly completed animal study (such as carcinogenicity)
• a temporary halt of a trial for safety reasons if the trial is conducted with the same investigational medicinal products in another country by the same sponsor
• recommendations of the Data Safety Monitoring Board, if any, where relevant for the safety of participants
• in the case of advanced therapy investigational medicinal products, relevant safety information regarding the procurement or the donor

This information should be addressed through the reporting of events other than SUSARs. Such events should be discussed in the IB as well as the DSUR or protocol modifications as applicable, e.g. in safety sections of IB other than RSI, especially if relevant to the risk/benefit evaluation. This also holds true for any follow-up measures.

These events/observations are not to be reported as SUSARs, but they might require other action, such as urgent safety measures and their notification, a substantial modification or early termination of the trial. If the criteria for a substantial modification is not met and no protocol changes are required then a substantial modification should not be submitted and notification to the licensing authority by other means (for example via the Clinical Trial Helpline) is not required. However, such information should be included for information in the next substantial modification application.

Other potential SUSAR exceptions

There are certain scenarios where an exception to the usual SUSAR reporting requirements can be included in a protocol. All such exemption proposals must be clearly detailed in the protocol and can only be put in place following approval by the licensing authority and ethics committee. Failure to seek such approvals prior to implementing any exceptions may result in a serious breach.

1) Exemption can be proposed for reports of deaths or SAEs also considered primary efficacy endpoints in trials with high mortality or high morbidity, where these efficacy end-points could also be SUSARs (and the integrity of the clinical trial may be compromised if the blind is systematically broken), and where such SAEs are therefore accepted to be ‘expected’ in the approved protocol. Under these circumstances the sponsor should clearly list which serious events would be treated as disease related and not participant to systematic unblinding and expedited reporting. For such trials, sponsors are strongly encouraged to appoint an independent DSMB in order to review safety data on the ongoing trial on a regular basis and, when necessary, to recommend to the sponsor whether to continue, modify or terminate the trial. The composition and operation of the DSMB should be described in the protocol. A specific adjudication committee or other safety review committee should also be considered, which includes members with specific expertise relevant to the endpoints. The DSMB/committee should regularly review emerging safety data, with a specific focus on any SAEs or SARs that are part of the primary endpoint. If a safety signal is identified then further review is recommended and any appropriate actions should be taken. This may include unblinding of events and making a determination on whether any events should be reported as SUSARs.

Example: A phase 3 randomised, double-blind, placebo-controlled, multicentre trial is evaluating drug X versus placebo, with a primary endpoint of reducing the risk of expanded MACE (cardiovascular death, non-fatal MI, non-fatal stroke and urgent coronary revascularization requiring hospitalization) in the overall study population. The protocol includes a safety section which defines AE and SAE recording and reporting. There is a specific section regarding endpoint related events that states that integrity of the study may be compromised if the blind is systematically broken for SUSARs that could also be primary efficacy endpoints. The usual rules for unblinding will not be followed for any SUSAR if it could represent one of the listed endpoints. An independent DSMB will review data on an ongoing basis and their opinion and recommendations will be notified to the sponsor. The study also details an independent cardiovascular adjudication committee who will specifically review all cardiovascular events in a blinded manner, highlighting that any recommendation by the adjudication committee for unblinding will be followed and all events that subsequently qualify as SUSARs will be reported to the licensing authority.

2) Exemption can be proposed for reports of deaths or SAEs considered as disease related events in the authorised protocol. However, careful assessment should be performed in cases where disease-related events appear to be enhanced by the IMP. A causality assessment is required for each SAE, and if the investigator considers a disease-related event to also be IMP- related and the event is both serious and unexpected then it must be reported as a SUSAR.

Example A: An application for approval of a clinical trial of an IMP targeting an oncology indication is submitted. The protocol clearly states that disease progression is not to be recorded as an SAE. The application is reviewed and is not approved by the licensing authority and ethics committee. A request for further information is issued requesting an update to the protocol. The sponsor complies, adding wording to clarify that if an SAE is considered unequivocally disease related then it will not be recorded as an SAE unless it is considered more severe than expected in the trial population or if it is considered related to the study drug. 

Example B: A sponsor is conducting a trial in a rare, inherited, autosomal recessive disease characterised by a disrupted lipid profile. There is the potential for potentially fatal myocardial infarction. The protocol clearly identifies this event as expected in the trial population, independent of the IMP. However, it further clarifies that any fatal myocardial infarction will be considered unexpected and reported as a SUSAR. Non-fatal myocardial infarction associated SAEs, as listed in the protocol, will be reviewed by an independent DSMB and compared to the expected rate of myocardial infarction associated events from natural history data (as stated in the protocol). If the aggregate analysis indicates that an event is occurring more frequently or at a greater severity than expected, then the event will be reported. The protocol is approved by the licensing authority and ethics committee.

Annual safety reporting

Legal basis

Under regulation 35 of the Clinical Trials Regulations, for each IMP tested in a clinical trial in the UK, the sponsor must provide the licensing authority with an annual report on the safety of the participants receiving the product. This annual report should be in the form of a Development Safety Update Report (DSUR). This requirement includes IMPs tested in clinical trials approved via [automatic authorisation (notifiable trials) or where the DSUR includes a combination of both notified and non-notified trials.

A single DSUR may cover multiple trials as it relates to a single IMP and not a specific trial. A trial specific DSUR may be accepted by exception (see example 1, below). Please note that this regulation does not apply: 

• to non-investigational medicinal products (NIMPs): however, per regulations A32 and 35 of the Clinical Trials Regulations, the DSUR for an IMP must include records of, and evaluation relating to, any serious adverse reactions and serious adverse events which have occurred in clinical trials during that year. Serious adverse events or serious adverse reactions with a suspected causal association with a NIMP should be included in the DSUR for the associated IMP. 

• in cases where the IMP is used in a single trial with a duration of less than one year that concludes before the end of the reporting year (defined below) 

In addition to the DSUR, the licensing authority may ask for a list of SARs and SAEs that have occurred at any time during the reporting year to be provided within 30 days of the request (or another timeline specified by the licensing authority). This may follow review of a DSUR, for example, or at any other time if a safety concern regarding a trial or its participants has come to its attention.

Signal management

A signal management process is a set of activities performed to determine whether there are new risks associated with an active substance or a medicinal product or whether known risks have changed, and includes any related recommendations, decisions, communications and tracking. This is similar to the pharmacovigilance practices which should be in place for marketing authorisation holders of licensed products, but can be adapted accordingly for products still in clinical trials and under development. In order to undertake signal detection, good pharmacovigilance should be built into the systems from the start; protocols and risk assessments should consider the key elements of safety reporting and facilitate the collection and review and reporting of all relevant safety information.

Sponsors should use the DSUR to present a comprehensive annual review of pertinent safety information collected during the reporting period and to evaluate whether it is consistent with the previous knowledge of the safety profile of the investigational drug. Taking into consideration the safety data from the new reporting period and the cumulative data recorded from the Development International Birth Date the sponsor should provide an interpretation of the information and its implications in terms of risk mitigation strategies. While it is understood that signal detection can occur through various means and that the DSUR should not be used to communicate new safety issues (which should be done via updates of the investigator’s brochure and, if applicable, via urgent safety measures) it should describe the actions taken to address safety concerns identified during the reporting period.

There is a need for sponsors to be more transparent about how they have reviewed, evaluated and interpreted the data included in a DSUR. The increased quality of the information included in the DSUR will facilitate the regulatory review process, will reduce additional requests of information from the regulatory authorities and ultimately demonstrate that the investigational drug is used in a safe manner.

Sponsors should take a risk proportionate approach to the presentation of safety data and signal management. An investigator-led single location phase 4 trial, for example, may require minimal signal management since the safety profiles of the IMPs should be largely already established. Where the product is marketed by the sponsor, the ongoing safety review will fit in with the signal detection procedures already in place (however, it should be ensured that these include the clinical trial data, not just the post-marketing information). However, a novel IMP in multiple phase 2 trials would be expected to have more extensive signal management processes in place. External sources of data such as scientific literature, may also need to be consulted and should form part of the process as relevant.

In addition to the processes in place for signal detection, the sponsor should outline any subsequent actions that may be required, highlighting if appropriate mitigation is already in place. Actions may include adding an event as an adverse event of special interest (AESI), additional safety assessments or additional timepoints for assessments already in place, more frequent DSMB oversight, an USM or temporary halt, as well as how the safety concern is communicated to locations and investigators. Consideration should also be in place for future signal management. Co-ordination of a safety signal across all ongoing trials is expected.

Content of the DSUR

Cover letter

Each submission should include a cover letter with the following:

• a list of all the IRAS IDs (for trials approved through the combined review process) or EudraCT numbers (for trials not approved through the combined review process) of trials covered by the DSUR
• an email address for correspondence
• the submission reference number in the format: DSUR-[5-digit MHRA company number]-[IMP name]-[Payment date DD/MM/YYYY] (for a trial-specific DSUR using multiple IMPs, only include one IMP in the submission reference)
• if applicable, a statement that the DSUR covers a period of less than one year, to align the international and development international birth dates

DSUR content

The DSUR should follow the headings in section 3 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance on Development Safety Update Report (E2F), clearly indicating if a section is not applicable. ICH E2F can also be referenced for additional detail on the content outlined below.

Per regulations A32 and 35 of the Clinical Trials Regulations, the DSUR must include the following:

• records of any serious adverse reactions (SARs) and serious adverse events (SAEs) which have occurred in clinical trials during that year, including suspected SUSARs, preferably provided as an aggregate summary tabulation
• evaluation of these SARs and SAEs, which should be from a global perspective, including any limitations to the evaluation, and evaluation of any changes in the overall risk-benefit
• records of any measures taken to investigate, minimise and prevent the risks presented by SARs and SAEs
• a detailed description of the assessment and management of any serious or non-serious safety concerns, including (but not limited to) temporary halts, actions taken by another regulatory authority, urgent safety measures, serious breaches, Dear Investigator letters, and specific non-clinical or clinical events

Per regulation A32 of the Clinical Trials Regulations, the above relates to not only trials conducted in the UK but also non-UK trials of the same IMP by the same sponsor or by a sponsor that is part of the same parent company as, or is jointly developing the IMP with, the sponsor of the UK trial.

It is also strongly recommended that the sponsor includes:

• line listings of the SARs that occurred in the reporting period or justification if not included (for example, if the safety evaluation narrative is sufficient to provide an overview).

• a description of the overall safety profile of the IMP(s), and a summary description of the processes implemented to monitor the overall safety profile of those products;
• a list of deaths from the reporting period and a narrative evaluating those deaths;
• as a region-specific appendix, a discussion of the safety review and safety signal review processes (or, where signal evaluation is not possible or appropriate, a justification for not including this). This should include:
  • the latest version of the full IB, particularly if there have been updates during the reporting period. Any other versions of the IB should also be included if multiple versions have been in place throughout the reporting period
  • a description of surveillance processes for reviewing and identifying potential new safety signals and updating existing safety signals, including the frequency of data review and the person responsible for reviewing it, the type of data source reviewed and the potential actions that may need to be taken as a result. The criteria used for determining the addition or deletion of expected terms to the RSI should also be described
  • the outcome of the safety signal review process during the reporting period, including a brief description of each potential new safety signal, the date when the sponsor became aware of the signal, the status of the signal at the end of the reporting interval (closed or ongoing), the date when the signal was closed (if applicable), the source of the signal, a brief summary of the key data, and plans for further evaluation and actions taken (i.e. proposed risk mitigation strategies). This should be provided in a tabular format, such as Appendix C of ICH E2C(R2) (see also example below). The possible decisions regarding a signal are:
• the signal is closed because the signal evaluation has been completed during the reporting period. The outcome of evaluation can be that the signal is refuted because the sponsor concluded that there is no causal relationship with the investigational drug. In this case the sponsor is expected to explain why the signal was refuted. Alternatively, the signal is closed because it is considered to be either a potential or an identified risk. In this case the sponsor should describe how the risk will be mitigated. Reference to either section 3.18 and/or 3.19 of the DSUR is acceptable.
• the signal is kept open because additional surveillance is needed to determine whether it can be closed or whether an association with the investigational drug can be suspected (potential risk) or is confirmed (identified risk).

Example of signal outcome review table

Signal term	Date detected	Status (ongoing or closed)	Date closed (for closed signals)	Source of signal	Reason for evaluation & summary of key data	Method of signal evaluation	Action(s) taken or planned
Anaemia	4 March 2015	Ongoing	N/A	Single serious case	The signal consisted of a single report of…	Individual case analysis; Review of relevant scientific literature. Reassessment of preclinical and clinical development safety data	Review at the next Safety Review Team Meeting

To illustrate the principles above, below are examples describing acceptable approaches to preparing a DSUR.

• Example 1: The DSUR is for two licensed medicines used in a non-commercial, academic-sponsored phase 2 trial that is in its third year and involves a single investigator and location. The DSUR is trial specific and this has been justified: the sponsor is non-commercial and is not intending to license the drug further in any way, the trial is not supported (financial or otherwise) by a commercial company, and the trial sponsor is not conducting any other trials with the IMP. During the reporting period, 20 participants have been dosed and there was a single SAR and two SAEs. The DSUR includes an aggregate table of SAEs and SARs and a narrative that clearly describes the serious events in the reporting period, including additional context for events seen in prior years and the known safety profile of the products. The narrative also describes the emerging safety profile in the trial, with consideration for the trial indication. No line listing is provided and this is justified based on the small number of events seen and the lack of reported SUSARs or actions taken for safety reasons.
• Example 2: A commercial sponsor is conducting a global development plan for an unlicensed IMP, including ongoing trials in both phase 2 and 3 and including two different indications. During the reporting period there have been multiple SAEs and SARs, including several SUSARs, and an urgent safety measure was taken in response to a new safety signal. The DSUR provides aggregate tables for SAEs and SARs in the reporting period, one per indication, as well as tables for cumulative events since the development international birth date. The narrative clearly describes the new events and actions taken, and the sponsor has included evidence of signal detection activities undertaken internally. Line listings for all SARs are included for the reporting period, separated by indication. SUSARs are clearly indicated and a narrative for each SUSAR is included. An update to the overall risk-benefit per indication is also included and remains acceptable.
• Example 3: A non-commercial sponsor is conducting 2 trials using the same IMP and which are only being conducted in the UK. The IMP is being developed by a commercial sponsor which is conducting other trials both in the UK and other global locations. The commercial sponsor also has overall responsibility for global safety oversight of the IMP. The non-commercial sponsor has contacted the commercial sponsor and will provide all relevant data to them in order for the commercial sponsor to submit a single DSUR for the IMP. The non-commercial sponsor therefore does not submit any IMP specific or trial specific DSUR(s) but documents evidence provided by the commercial sponsor that the DSUR has been submitted. In this example it should be noted that this is the strongly recommended approach.

Confirmation of payment

Fees applicable to submission of a DSUR must be paid prior to submission. To pay these fees, please refer to the guidance on paying online before submitting an annual safety report. Following payment, a receipt will be sent by email to the payee which must be included in the submission in the submission in its original format as a standalone document that serves as proof of payment. Failure to provide evidence of payment will result in the submission being invalidated.

Submitting a DSUR

Timelines for submission

Under regulation 35 of the Clinical Trials Regulations, the sponsor must submit the DSUR to the licensing authority (but not the ethics committee) within 60 calendar days from the day after the end of the reporting year, defined as:

• the international birth date: for products with a marketing authorisation, the anniversary of the date on which the marketing authorisation was issued
• the development international birth date: for IMPs without a marketing authorisation, the anniversary of the earliest date on which a clinical trial using the same IMP and that has the same sponsor was authorised in any country (or a date designated by the sponsor that is linked to the commencement of the first clinical trial, if the country has no formal authorisation process)

The international birth date and development international birth date can be aligned by submitting a DSUR covering a period of less than one year (however, the dates cannot be aligned by submitting a DSUR covering a period of more than one year). The next DSUR should then be submitted within 60 calendar days of the aligned date.

Annual submission of DSURs must continue until there are no ongoing trials in the UK for the IMP covered by the report (i.e. all global end of trial notifications have been submitted).

Process for submitting a DSUR

Please note that as DSURs relate to the IMP and not a specific trial, a report may cover multiple clinical trials. In this case, the DSUR should only be submitted once.

To submit a DSUR to the licensing authority:

• if at least one of the clinical trials covered by the DSUR was approved through the combined review process, submit the report through IRAS. Guidance on using IRAS to submit a DSUR can be found in the Step-by-step guide to using IRAS for combined review
• if all of the clinical trials covered by the DSUR were approved through separate applications to the licensing authority and the ethics committee, submit the report through MHRA Submissions

After submission, the DSUR undergoes validation checks. The sponsor will be informed of the outcome of these checks by email (and through IRAS, if this route of submission was used). If the submission is invalid, an informal request for information to address the deficiencies will be issued. However, if these deficiencies remain unresolved, the submission will be invalidated and the sponsor will need to resubmit the DSUR with the deficiencies corrected.

Valid DSURs are reviewed and requests for additional information may be made by email (and through IRAS, if this route of submission was used), with a timeline for response set by the licensing authority. Once the licensing authority has sufficient information, the sponsor will be informed by email (and through IRAS, if this route of submission was used) that the DSUR has been accepted.

Management of the IB and RSI in relation to the DSUR

The DSUR should contain, in an appendix, the RSI in effect at the start of the reporting period. The RSI in effect at the start of the reporting period serves as RSI during the reporting period. If there are significant changes to the RSI during the reporting period they should be listed in the DSUR. Moreover, in this case the revised RSI should be submitted as an attachment to the report, in addition to the RSI in effect at the start of the reporting period. Despite the change to the RSI, the RSI in effect at the start of the reporting period serves as RSI during the reporting period.

Urgent safety measures (USMs)

Initial phone call with the licensing authority

An urgent safety measure is an action that the sponsor and investigator may take in order to protect the subjects of a trial against any immediate hazard to their health or safety (for example, an organisation identifies that there is a significantly higher incidence of death at one UK location, and as a result suspends recruitment at that location as an urgent safety measure).

Once trial participants have been recruited, appropriate USMs may be taken at any time to protect the participants from any immediate hazard to their health or safety. These modifications may be implemented without first notifying the licensing authority and ethics committee.

No later than 3 days after the measures are taken (but ideally within 24 hours), the sponsor should contact the licensing authority through the Clinical Trial Helpline (020 3080 6456) to discuss the USM. The sponsor will be asked to provide, or to provide as soon as possible, the following information:

• IRAS ID (for trials approved through the combined review process) or EudraCT number (for trials approved through separate applications to the licensing authority and the ethics committee) of the trial for which the USM has been taken, any of the sponsor’s other ongoing trials with the same IMP, and any trials the sponsor is aware of that are run by a different sponsor and are affected by the USM
• the details of the affected IMP(s), including name, class, dose and duration of dosing, and route of administration
• the nature of the safety concern and whether it has been reported as a SUSAR
• details of the measures taken and the rationale for those actions
• the number of UK participants currently or previously receiving the IMP, and the number of UK and non-UK participants affected by the USM
• any actions taken as part of the USM in trial locations outside the UK or in a non-UK trial using the same IMP

If the sponsor is unable to report the USM by telephone, they should email clintrialhelpline@mhra.gov.uk with contact details, the trial’s IRAS ID or EudraCT number, a description of the USM, and an explanation as to why it was not reported via phone. The licensing authority will then contact the sponsor with further actions.

Failure to notify the licensing authority of the implementation of an USM for safety reasons may be considered a serious breach.

Written notification of the USM

Following the initial telephone conversation with the licensing authority, regardless of whether the measures discussed are informally agreed to be a USM, the sponsor must provide written notification to the licensing authority, describing the events requiring  action to be taken, and the measures taken in response to those events, including any additional actions requested by the licensing authority.

Per regulation 30 of the Clinical Trials Regulations, this must be done within 7 calendar days from the date the measures are taken, or as soon as possible during any period where a disease is pandemic and is a serious or potentially serious risk to human health.

To submit a written notification:

• if any of the clinical trials affected were approved through the combined review process, submit through IRAS. Guidance on submitting an urgent safety measure notification through IRAS can be found in the Step-by-step guide to using IRAS for combined review
• if all of the clinical trials affected were approved through separate applications to the licensing authority and the ethics committee, email the notification to the licensing authority (clintrialhelpline@mhra.gov.uk)

The licensing authority will review the written notification and may request additional information by email (and through IRAS, if this route of submission was used). Once the licensing authority has sufficient information, it will decide whether the measure taken is a USM and communicate the outcome to the sponsor by email (and through IRAS, if this route of submission was used).

Substantial modification covering the urgent safety measure

If the licensing authority agrees that the measure is a USM, the sponsor should submit a substantial modification that covers the USM (with no additional changes) using the [same process as other applications for a substantial modification] (although in this case the modifications will have already been implemented) within 2 weeks of the date on which the licensing authority was first informed (via telephone) of the USM. The sponsor should agree any potential delays with the licensing authority during the initial or a follow-up telephone call.

If the licensing authority does not agree that the measure is a USM, it will confirm with the sponsor whether any further actions are needed.

The process is summarised in Figure 4: Flowchart summarising the process of notifying the licensing authority about a potential urgent safety measure.

Serious breaches

Legal basis

Under regulation 29A of the Clinical Trials Regulations a sponsor must notify a serious breach to the licensing authority.

This obligation applies to any serious breach of either:

• the conditions and principles of good clinical practice in connection with that trial
• the protocol relating to that trial

A “serious breach” is considered to be any breach which is likely to effect to a significant degree either:

• the safety or physical or mental integrity of the participants of the trial
• the scientific value of the trial

The judgement on whether a breach is likely to have a significant impact on the scientific value of the trial depends on a variety of factors, for example, the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the data from the analysis, etc. It is the responsibility of the Sponsor to assess the impact of the breach on the scientific value of the trial.

Report a serious breach

The sponsor (or their delegate) must notify the licensing authority of a serious breach at the latest within 7 calendar days of the sponsor becoming aware of the serious breach.

It is acknowledged that some serious breaches may be identified and reported by vendors and/or investigator locations to the sponsor, who may disagree with the serious breach assessment. Alternatively, the vendor may become aware that the sponsor has committed a serious breach. In these cases, vendors will need to consider what actions to take; this may include direct reporting to the licensing authority. It is expected that organisations exercise due diligence and as such make every effort to ensure that both themselves and the sponsor comply with the legislation, and retain documentation as evidence of this attempt.

It is the responsibility of the Sponsor to take appropriate corrective and preventative actions in response to the serious breach, and to document these actions. Actions may also be taken by the licensing authority.

For information on how to report serious breaches, please see Good clinical practice for clinical trials.

Temporarily suspending a trial

A temporary halt of a trial is a stoppage of the trial which is not envisaged in the approved protocol and where there is an intention to resume it. This can be halt of the trial as a whole, of part of a trial, or a stoppage at one or more trial locations to protect participant safety or avoid potential harm to participants.

Please note that a notification of a temporary halt is not expected where:

• recruitment or trial conduct is temporarily paused for logistical reasons, for example, trial team unavailability or a transient supply issue. However, where long standing issues impact the trial such as unavailability of the IMP during to manufacturing issues, for example, then temporarily suspending the trial should be considered
• a trial is ‘paused’ to determine if a temporary halt is warranted or necessary. In this case, the notification to the licensing authority is not expected unless the investigation concludes that an “official” temporary halt is warranted. Permission to restart following the pause is not required. Such investigations must be conducted without delay, otherwise a substantial modification notifying of the halt should be submitted

To temporarily suspend a trial or part of a trial, submit an application to approve a Route A substantial modification, clearly explaining what aspects of the trial have been stopped and the reason for the suspension. This should be done within 15 calendar days of the trial being temporarily halted.

A temporary halt can also be part of an urgent safety measure (USM). In this case, the notification of the temporary halt of a trial should be done via the usual process and following the usual timelines for reporting USMs. Failure to notify the licensing authority of the implementation of a temporary halt for safety reasons may be considered a serious breach.

During the temporary halt, participants should be monitored or followed up. While the trial is halted, the issues of concern should be assessed and revisions to be made to the clinical trial protocol may be required. After this analysis is completed, and reassurance that any potential problem may be solved or mitigated, the sponsor could either restart or end the CT.

To restart a trial after a temporary halt, submit a second application to approve a substantial modification. This application should include evidence that it is safe to restart the trial, including conclusions of the analysis, the mitigation measures if applicable and an updated benefit/risk assessment.

No fixed limit applies to how long a trial can be suspended for, however, the licensing authority and ethics committee will take the suspension duration into account when assessing the application to restart the trial.

If the trial is not restarted, guidance on declaring the end of a clinical trial should be followed.

Predefined halts in a protocol

There are scenarios where a temporary halt in a trial is predefined in a protocol as a precautionary measure to safeguard the trial participants, for example in the event safety data meets predefined dose escalation stopping rules in a first-in-human trial. In these cases, the protocol should clearly outline decision points and criteria for the situation where stopping rules are met. In protocols that include both options of pausing (as outlined in the section above) and halting the study, it is important that the ‘pause’ criteria and the definitive stopping rules (halting criteria) are clearly differentiated and defined. It is also expected that protocols clearly state that in the event a predefined stopping rule is met then a substantial modification will be submitted to allow trial restart if restart is deemed appropriate: it is not acceptable to make reference to following local guidance in this scenario.

Halts based on predefined rules do not require submission of a substantial modification to the licensing authority for a temporary halt. However, deviations from the pre-specified dose escalation or other decision-making criteria would warrant the submission of substantial modification. 

However, in the event the sponsor wishes to restart the trial after protocol defined stopping is met then a substantial modification is required to allow that restart. This application should include evidence that it is safe to restart the trial, including conclusions of the analysis, the mitigation measures if applicable and an updated benefit/risk assessment.

Published 25 June 2025