Pharmacovigilance (PV) of authorized medicinal products is regulated by a series of regulations, directives, laws, and guidelines. These rulings do not relate to pharmacovigilance of investigational (IMP) and non-investigational medicinal products (NIMP) used in clinical trials, which is not less obligatory. Instead, the PV of clinical trials is an inherent albeit subordinate aspect of Good Clinical Practice (GCP).

Although relying on the (process) resources put in place by the sponsor for Eudravigilance (EV) reporting, PV of clinical trials requires its own GCP-compliant trial specific provisions: risk-based PV-Quality Management, review of the Safety Reference Information in the Investigator Brochure, review of the PV-information and -instructions in the Clinical Trial Protocol, Investigator Training and Instruction, on-study capture and analysis of safety signals, expert review of SAE-reports, expedited handling of SAE/SUSAR-reports, etc.

In consequence, some six years ago, ACPS initiated, validated, and implemented SOPs pertinent to orderly PV of clinical trials. When writing these SOPs it became obvious that there was need to provide more background and explanation to the SOP-rulings in order to facilitate their implementation and adherence. This resulted in a series of training modules on CT-PV and ultimately to an extensive CT-PV-Manual.

ACPS’ extensive Manual on Pharmacovigilance for Clinical Trials is available to you at no cost on request by E-mail (RE: “CT-PV Manual”).

{27.Mar.2018 | ACPS-CdM}

Pharmacovigilance (PV) for clinical trials (CT) is regulated differently from the PV provisions for authorized medicinal products. Instead, CT-PV is an inherent albeit subordinate aspect of Good Clinical Practice (GCP) and is subject to the international and national regulations on the orderly conduct of clinical trials and GCP-compliance.

The resulting CT-PV duties and responsibilities are inherent to the role of the sponsor but can be delegated (acc. GCP-Directive Section 3 Article 7 Item 1-2 | EU Clinical Trial Regulation Article 71). Delegation needs to account for two operational functions:

1. vigilant surveillance and
2. compliant (i.e. ‘expedited’) reporting of time-sensitive safety signals.

These functions are complementary but distinct. In order to manage these two functions properly, we recommend defining two operators:

1. A trial-specific Clinical Trial Safety Officer (CTSO) who establishes and directs a trial-specific GCP-compliant PV quality management system (PV-system) in extension to the overall quality management of the trial and
2. A trial-unrelated Eudravigilance Responsible Person (EV RP) EV RP who is responsible for EV-reporting

These functions are operationally distinct, but can be assumed by the same person – see next.

{12.Apr.2018 | ACPS-CdM}

The Clinical Trial Safety Officer (CTSO) is the party who is responsible for planning, managing, documenting, and reporting a GCP-compliant PV Quality Management System (QMS) for a trial. This function is not specifically defined in GCP, but it accounts for the need and duty to establish a GCP-compliant PV-QMS. There is no regulated name for this function; at ACPS we are used to refer to this function as the ‘Clinical Trial Safety Officer’, but surely other names might be used.

The CTSO is the named person who establishes and directs the PV-QMS in extension to the overall quality management of the trial. The CTSO represents the sponsor in all aspects pertinent to PV for the trial (including liaison with the sponsor, investigators, competent authorities, and ethics committees). In consequence, the CTSO is the PV-contact to be named in the Clinical Trial Protocol. In the EudraCT-application (“Module 1”) – Section G.5 (“Organisations to whom the sponsor has transferred trial related duties and functions”) the CTSO is to be listed under item G.5.1.19 (“Other duties subcontracted”). The CTSO is an authority established within the quality management system of the trial and is named to this purpose by the sponsor either within his organisation or as delegated authority. The responsibility of the trial’s CTSO is distinct from that of the sponsor’s EudraVigilance Responsible Person (EV RP – see next), but both authorities can be assumed by one person.

Depending on how GCP-duties and responsibilities are otherwise assigned and regulated, we consider it advisable that a CTSO is named and that this CTSO is responsible at least for the following:

1. Review of investigator and/or CRO contracts: Although the CTP takes precedence with regard to instructing the investigator and his team about the investigators’ PV-responsibilities and –duties, the CTSO will review/provide input to the contract template to ensure that these responsibilities and duties are properly addressed.
2. IB-Review (as Reference Safety Information [RSI] acc. Art. 2(g) of the EU Clinical Trial Directive and Art. 8(1) of the EU Commission Directive 2005/28/EC): The CTSO provides input to and/or reviews PV-pertinent IB-information e.g. Section “Summary of Data and Guidance for the Investigator” (ICH E6(R2) Section 7.3.7) also to include specification of adverse drug reactions that need to be seen as ‘expected’ (e.g. EudraLex Volume 10 CT-3 Section 7.2.3.2), and – if applicable – specification of non-serious SAE (acc. EudraLex Volume 10 CT-3 Art. 115).
3. CTP-Review: input to and/or review of PV-pertinent information in the CTP i.e.
   • Summary of the benefit:risk evaluation (acc. GCP E6 (R2) Section 6.2.2 and 6.2.3)
   • Definition of ‘adverse events’ (AE), ‘serious adverse events’ (SAE), ‘adverse drug reactions’ (ADR), ‘serious adverse drug reactions’ (SADR), ‘suspected unexpected serious adverse drug reactions’ (SUSAR) (acc. ICH E2A Section 2)
   • Criteria of ‘seriousness’ particularly with regard to the category “medically significant” acc. ICH E2A and the category “other significant adverse events” acc. ICH E3 (if applicable)
   • Criteria of ‘causality’ (acc. ICH E2A Section 2, EU Clinical Trial Directive – Article 2, EU Clinical Trial Regulation – Annex III Section 2.1)
   • Criteria of ‘expectedness’ with reference to the RSI (acc. ICH E2A Section 2, EU Clinical Trial Directive – Article 2, EU Clinical Trial Regulation Section Annex III Section 2.2)
   • Criteria for reporting by AE-category (seriousness, intensity/severity, causality, AE-intervention, outcome, etc.)
   • Definition of the time window of PV (when does CT-specific PV start, when does it end) and provisions for follow-up of AE and SAE unresolved at the ordinary end-of-trial visit
   • Instruction that the investigator must report any SAE immediately to the PV CTSO (contact details to be specified)
   • Instruction that the investigator must report any pregnancy and must provide for follow-up thereof in trial participants who are or have been exposed to the investigational medicinal product
4. Alignment with the trial’s Quality Management Plan (i.e. the CTSO ensures that the Trial Manager [CRO/CTM] implements following requirements):
   • Site/investigator selection based on qualification considerations pertinent also to orderly PV-management at the site
   • The site/investigators are provided with an Investigator Site File that contains the PV-relevant documentation: IB, CTP, SAE- and Pregnancy-report templates, copies of the guidelines pertinent to GCP-compliance
   • The site/investigators are provided with due training on trial-specific GCP-, CTP- and PV-compliance/adherence at trial initiation and/or at the investigator meeting (optionally: which the CTSO may attend)
5. Alignment with the Monitoring Plan and Review of PV-relevant Monitoring-Findings:
   • The monitor checks and collects the investigators’ declarations of IB- and CTP-receipt
   • The monitor checks that AE-information is entered without un-due delay into the CRF and that the AE-information in the CRF is up-to-date and well-sourced
   • The monitor checks that clinical laboratory safety reports are reviewed by the investigator without undue delay by the investigator and that due follow-up is given in the event of clinically significant abnormalities
   • The monitor checks and reports (at each on-site visit) whether any GCP-, CTP- or PV-violation occurred; the Trial Manager checks whether these deviations need to be referred to the CTSO; also, the Trial Manager (in collaboration with the SMO) implements due action for prevention and correction of such defects.
   • The monitor checks and reports (at each on-site visit) whether any noteworthy safety–relevant event occurred; this information is to be reviewed by the Trial Manager and referred to the CTSO if and as needed.
6. Instruction of and liaison with the Investigator: the CTSO instructs the CRO and/or investigator:
   • To train the site staff with regard to the need for PV and implications thereof with regard to the provisions for an orderly conduct of the study
   • To survey the site staff with regard to their compliance with GCP-, CTP- and PV-requirements  and to take immediate corrective and preventive action in the event of defect thereof
   • To pay due attention on safety-relevant findings upon physical examination, measurement of vital functions (blood pressure, pulse rate, body temperature [if applicable]), ECG and other on-trial investigations if applicable (e.g. spirometry, etc.)
   • To review clinical laboratory reports without delay (review to be document by dated signature on a paper report and to follow-up on abnormal values considered to be clinically significant (i.e. clinical laboratory abnormalities that need to be reported as AE)
   • To enter AE without undue delay in the CRF and to keep these records up-to-date and well-sourced also with regard to related circumstantial information such as (past) medical history, (present) co-morbidities and co-medication
   • If no eCRF is used: to keep an on-study data table (e.g. xlsx) of the AE and to transmit this table at agreed time intervals to the CTSO
   • To report SAE and pregnancies immediately to the contact named in the clinical trial protocol and by means of the report templates provided to this purpose
   • To collaborate closely with the PV CTSO with regard to the follow-up of SAE and pregnancies
   • To report any premature discontinuation from the trial due to AE without delay to the CTM/CRO; any such occurrence will then be reported by the CTM/CRO to the CTSO
   • Optional: to ensure that appropriate technical infrastructure and qualified personnel are available for the management of medical emergencies
7. Instruction of and liaison with the Clinical Laboratory: The CTSO instructs the clinical laboratory with regard to the following
   • To establish and maintain an orderly GCP-compliant documentation of the quality management of the CLINLAB-services
   • To provide the investigators with precise instructions for orderly sampling, sample processing, sample storage and sample shipment/transfer
   • To communicate any change in test procedure and/or test normal ranges without delay to the investigator, the CRO/CTM, and the Data Manager
   • To set-up a reporting system of the individual but pseudonymised results of the clinical laboratory testing to the investigator; on these reports, test values outside of the normal range should be highlighted. Sample issues (e.g. haemolytic samples, lipaemic or icteric samples) should be commented upon.
   • To set-up a reporting system of clinical laboratory ‘alerts’ i.e. findings that must be reported to the investigator immediately since they might represent an urgent medical risk to the trial subjects
     (e.g. severe hypoglycaemia, severe hypokalaemia, highly elevated liver enzyme levels, etc.).
   • Optional: to set-up with the Data Manager and CRO/CTM an electronic on-study reporting system (e.g. csv-Table) of the clinical laboratory test results by subject and visit
8. SAE-report analysis & processing: Irrespective of its expectedness and causality, any AE that qualifies as ‘serious’ in accordance with the CTP-definitions needs to be reported without delay (within 24 h of becoming aware of the event) by the investigator to the CTSO (in compliance with the EU Clinical Trial Directive Article 16(1) and EudraLex Volume 10 CT-3 Section 4). Related AE-categories (acc. EU Clinical Trial Directive Article 2(o) and EudraLex Volume 10 CT-3 Section 4.2.2 Article 24) need to be defined in the CTP, which also names the CTSO as the investigator’s contact for SAE-reporting. Already when raising the initial report, the investigator should make a reasonable attempt to categorise the causality of the SAE. Assignment of causality is mandatory not later than at the first follow-up of the initial report; this does not preclude that the investigator may wish to revise his initial assessment of causality once more follow-up information becomes available. However, a conclusive statement of causality is due not later than five days after becoming aware of the event.
9. SUSAR-assessment and -processing: Reporting to the Clinical Trial Module of the EudraVigilance database (EVCTM) in compliance with Article 17(1)(a), (b) and (d) of the EU Clinical Trial Directive, EudraLex Volume 10 CT-3 (Chapter 7 – Article 37-42) including ‘indirect’ reporting to the national CA, is privileged in this sense that it can only be executed by the authorised and certified EudraVigilance Responsible Person (EV RP) of the sponsor, an authority, which is sponsor-specific, but trial-unrelated (see next). In such cases, the CTSO prepares the case report such that it is ‘fit for reporting’ by the EV RP. Reporting to the EC and investigators does not require EV RP authority and can be performed by the EVRP, the CTSO or both.

{27.Apr.2018 | ACPS-CdM}

AEs that require timely i.e. expedited reporting

Serious adverse events that qualify as “suspected unexpected serious adverse reactions” (SUSAR) are subject to timely (i.e. expedited) reporting to the Clinical Trial Module of the EudraVigilance database (EVCTM), the national competent authorities (CA) of the EU member states where the trial is conducted, the ethics committees (EC) and the investigators. Timing depends on whether the SUSAR is fatal/life-threatening (7 days rule) or not (15 days rule).

Details on the related rulings can be found under EU Clinical Trial Directive Article 17(1)(a), (b) and (d) and EudraLex Volume 10 CT-3 (Chapter 7 – Article 37-42). EudraLex Volume 10 CT-3 Chapter 7 also provides due specification on what is to be reported, when and how.

Note: The need for ‘timely’ reporting to CA, EC, and investigators applies also for a series of non-SUSAR safety findings acc. EudraLex Volume 10 CT-3 Art. 121 and the EU Clinical Trial Regulation Art. 48.
Such non-SUSAR relevant PV-findings subject to ‘timely reporting’ do not match the EVCTM framework and thus cannot be reported to EV. They should be reported to the CA (‘directly’), to the ECs and investigators. (see also EudraLex Volume 10 CT-3 Art. 123).

Role and assignment of the EV RP

The EudraVigilance Responsible Person (EV RP) i.e. the person who represents the sponsor interacting with Eudravigilance (EV) with regard to uploading pertinent safety reportsinto the Clinical Module of the EudraVigilance database (EVCTM). This is a central sponsor-based trial-unrelated authority.  Assignment of the EV RP depends on the sponsor’s regulatory status in the EEA as specified in EMA/353007/2016 (EudraVigilance Registration – Questions and answers – Mar.2017) –In brief:

1. For a sponsor, who is also a marketing authorisation holder (MAH) or a marketing authorisation applicant (MAA) in the EEA, the EU Qualified Person for Pharmacovigilance (EU QPPV) of the EEA headquarter of the sponsor’s organisation continues to be the organisation’s representative in the EV registration process. No additional registration of a responsible person for EudraVigilance (EV RP) is required.
2. For a sponsor (established in the EEA), who is not a MAH or MAA, an organisation’s representative for the EudraVigilance registration process (EV RP) should be appointed. Only one responsible person for EudraVigilance should be appointed by the sponsor for all clinical trials conducted by the sponsor in the EEA; in this event, the EV RP should be appointed by the ‘sponsor named person’ as identified in Section B 1.2 of the EudraCT-application.
3. For sponsors not established in the EEA, an organisation’s representative (EV RP) for the EudraVigilance registration process should be appointed. The EV RP does not need to reside in the EEA. Only one EV RP should be appointed for the sponsor for all clinical trials conducted by the sponsor in the EEA; the EV RP should be appointed by the legal representative of the sponsor as identified in Section B 2 of the EudraCT-application).

Whatever its prime assignment (see above), the role of EU QPPV / EV RP can be delegated by the sponsor to a service provider in compliance with Article 6 of the Commission Implementing Regulation (EU) No 520/2012 (“Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 article”), GCP-Directive Section 3 Article 7 Item 1, and EudraLex Volume 10 CT-01 Article 3 §19.

In the EudraCT-application (“Module 1”), the EV RP (whether delegate or not) is named in Section G.5 under item G.5.1.15 (“SUSAR-reporting”). In order to ensure continuity, the authority of the EVRP should be extended by naming a “trusted deputy” within the EVRP’s organisation who is also registered as EV user (as per EMA/288747/2016 – Mar.2017).

The assigned EV RP needs to have completed training to operate in the EVCTM environment and needs to have been registered as user of the reporting system:

1. Training: The EV RP is due to have completed certified training to operate in the EVCTM environment (eXtended EudraVigilance Medicinal Product Dictionary [XEVMPD] Data-Entry Tool [EVWEB]) – Note: Training needs to account for the major EV update scheduled for release Nov.2017 (see EMA/835422/2016 – EudraVigilance training plan – v4)
2. User registration: The EV RP (and his ‘trusted deputy’) is due to have completed user registration in accordance with EMA/286818/2016, EMA/353007/2016, and EMA/288747/2016.
3. Re-assignment: The EV RP assignment is sponsor-specific, but trial- and product-unrelated. Therefore, there might be interest and need to re-assign the EV RP authority once a trial (for which a specific EV RP delegate had been assigned) is completed. This re-assignment is subject to EMA/87465/2016.

Alignment of the EV RP with the CTSO

At ACPS we advocate that two distinct, but complementary functions are named for orderly Pharmacovigilance of Clinical Trials:

1. the Clinical Trial Safety Officer (CTSO) who directs the trial-specific quality managements system for pharmacovigilance of the trial as an essential, albeit subordinate aspect of the overall GCP-compliant quality management of the trial. The CTSO acts as primary contact named in the CTP, receives SAE-reports from the investigator, analyses and evaluates the information, organises due follow-up and clarification by the investigator and raises initial and follow-up reports (in compliance with ICH E2A) that are ‘fit for EVCTM-reporting’ (acc. ICHE2B and EMA GVP Module VI) by the EV RP.
2. the EudraVigilance Responsible Person (EV RP) i.e. the sponsor-specific trial-unrelated priviliged party for reporting of SUSAR to the EVCTM

The CTSO and EV RP operate conjointly (4-eye principle) to check and validate the ICSR for EVCTM reporting and follow-up thereof. Within this setting, the CTSO and EV RP will need to decide who is responsible to parties other than EVCTM.

“Serious” adverse events (SAE) are those AE that meet any of the criteria set by the EU Clinical Trial Directive Article 2(o), EudraLex Volume 10 CT-3 Article 24, and/or ICH E2A Section II.B.
As discussed next, the criteria of seriousness may be extended to other AE considered to be “important medical events” (acc. EudraLex Volume 10 CT-3 Article 26) or “medically significant” events (acc. ICH E2A Section II.B). SAE must be reported immediately by the investigator to the sponsor unless rulings were set a priori for not reporting certain SAE in such expedited fashion (see next topic).

SAE are subject to expedited reporting by the sponsor to EudraVigilance, Competent Authority, Ethics Committees, and investigators if they qualify as “suspected unexpected serious adverse reactions” (SUSAR). This applies to SAE that are “unexpected” while not listed in the IMP’s Reference Safety Information and that are “adverse reactions” with a reasonable causal relationship (see ICH E2A Section 3.A.1 and EudraLex Volume 10 CT-3 Art. 45 – see topic below).

Unexpectedness is defined as

• ICH E2A Section II.A.3: « Unexpected Adverse Drug Reaction = An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational medicinal product). »
• EU Clinical trial Directive Article 2(p) and EudraLex Volume 10 CT-3 Section 7.2.3.1 Art. 48: « an adverse reaction is “unexpected” if its nature or severity is not consistent with the applicable product information (e.g. investigator’s brochure for an unauthorised investigational product or summary of product characteristics for an authorised product) »
• Also, EudraLex Volume 10 CT-3 Section 7.2.3.1 Art. 50 adds: « Reports which add significant information on the specificity, increase of occurrence, or severity of a known, already documented serious adverse reaction constitute unexpected events »

Therefore, “expectedness” is unrelated to actions that might be likely to occur pursuant to the AIP’s known or suspected pharmacological actions:

• ICH E2A Section II.C « The purpose of expedited reporting is to make regulators, investigators, and other appropriate people aware of new, important information on serious reactions. Therefore, such reporting will generally involve events previously unobserved or undocumented, and a guideline is needed on how to define an event as “unexpected” or “expected” (expected/unexpected from the perspective of previously observed, not on the basis of what might be anticipated from the pharmacological properties of a medicinal product) »
• EudraLex Volume 10 CT-3 Section 7.2.3.2 Art. 51: « The expectedness of an adverse reaction is determined by the sponsor in the reference safety information (‘RSI’). 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 a medicinal product »

Instead, “un-/expectedness” is defined primarily whether or nor the ADR is listed Reference Safety Information (“source” per ICH E2A):

• ICH E2A Section II.C: « The following documents or circumstances will be used to determine whether an adverse event/reaction is expected:
  For a medicinal product not yet approved for marketing in a country, a company’s Investigator’s Brochure will serve as the source document in that country.
  2. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events. For example, an event more specific or more severe than described in the Investigator’s Brochure would be considered “unexpected”. Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis »
• EudraLex Volume 10 CT-3 Section 7.2.3.2:
  52: «The RSI is contained in the Summary of product characteristics (‘SmPC’) or the IB. The covering letter which is submitted with the application to the national competent authority should refer to the RSI.
  Art. 53. If the RSI is contained in the IB, the IB should contain a clearly-identified section to this effect. This section should include information on the frequency and nature of the adverse reactions.
  Art. 54. If the IMP has a marketing authorisation in several Member States concerned with different SmPCs, the sponsor should select the most appropriate SmPC, with reference to subject safety, as RSI.
  Art. 55. The RSI may change during the conduct of a clinical trial. This is typically a substantial amendment. For the purpose of SUSAR reporting the version of the RSI at the moment of occurrence of the SUSAR applies. Thus, a change of the RSI impacts on the number of adverse reactions to be reported as SUSARs. »

Responsibilities:

• EudraLex Volume 10 CT-3 Section 7.3.3 “Expectedness”:
  60: « Assessment of expectedness is usually done by the sponsor.
  Art. 61: The ‘expectedness’ of a serious adverse reaction is assessed in the light of the RSI
  Art. 62: If information on expectedness has been made available by the reporting investigator, this should be taken into consideration by the sponsor»

RSI in the context of yearly safety reporting:

• EU Clinical Trial Directive Article 17(2) and EudraLex Volume 10 CT-3 Section 8 “Annual Safety Reporting By The Sponsor To The National Competent Authority And The Ethics Committee”:
  124« Once a year throughout the clinical trial, the sponsor shall provide the Member States in whose territory the clinical trial is being conducted and the Ethics Committee with a listing of all suspected serious adverse reactions which have occurred over this period and a report of the subjects’ safety. »
• EudraLex Volume 10 CT-3 Section 8 Art. 127: « For details regarding annual safety reporting, including rules for unblinding, reference is made to the guideline ICH Topic E2F (Development Safety Update Report [DSUR]).
  128: The report should contain, in an appendix, the RSI in effect at the start of the reporting period (see ICH E2F Sections 2.6 and 3.20).
  Art 129: The RSI in effect at the start of the reporting period serves as RSI during the reporting period.
  Art. 130: If there are significant changes to the RSI during the reporting period they should be listed in the annual safety report. 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 (see above). Despite the change to the RSI, the RSI in effect at the start of the reporting period serves as RSI during the reporting period. »

RSI in the context of yearly IB review

• ICH E6 (R2): « The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB »

Recommended further reading

• Clinical Trial Facilitation Group (CTFG) – Q&A document – Reference Safety Information (Nov.2017)

{15.Jun.2020 U: 404.Mar.2021 | ACPS-CdM}

“Serious” are all AE that meet the criteria of the EU Clinical Trial Directive Article 2(o) and EudraLex Volume 10 CT-3 Section 4.2.2 Article 24, i.e. “Any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect”. Other AE may also need to be set as “serious” while “important medical events” (acc. EudraLex Volume 10 CT-3 Article 26), “medically significant” (acc. ICH E2A) or categorised as “other significant adverse events” (acc. ICH E3).

There are exemptions/extensions to this overall definition; they relax the ruling that SAEs need to be reported immediately by the investigator to the sponsor and that SUSAR need to be reported without delay (7- or 15-day rule) by the sponsor to EudraVigilance, CA, EC, and investigators:

1. ICH E6(R2) Section 4.11.1: « All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting »
2. EU Clinical Trial Directive Art. 16(1), EudraLex Volume 10 CT-3 Section 4.3 Art 28 & 31, and EudraLex Volume 10 CT-1 Section 2.5 Art. 48 provide for an exception to the general rule that the investigator must report any SAE immediately to the sponsor: « The investigator shall 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 »
3. Also, EudraLex Volume 10 CT-3 Art. 115 and the Clinical Trial Regulation Annex III Section 2.5 Item 21 regulate an important exemption to the rule of considering any fatal or life-threatening SUSAR to be subject for expedited reporting: « …. for trials in high morbidity or high mortality disease, where efficacy end-points could also be SUSARs or when mortality or another ‘serious’ outcome (that may potentially be reported as a SUSAR) is the efficacy end-point in a clinical trial, the integrity of the clinical trial may be compromised if the blind is systematically broken. Under these and similar circumstances, the sponsor should reach agreement in the authorization process as to which serious events would be treated as disease-related and not subject to systematic unblinding and expedited reporting ».

The applicable rulings provide for such exemptions, but they do not specify for which kind of AE they may be used.
If applicable, specifications and their justification need to be provided in the CTP and IB of the trial.

{27.Apr.2018 – Update: 06.Jun.2020 | ACPS-CdM}

An adverse drug reaction (ADR) is an adverse event (AE) to which the following applies:

• ICH E2A Section 2.A.2: « all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase “responses to a medicinal products” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. »
• EU Clinical Trial Directive Art 2(n) & EudraLex Volume 10 CT-3 Section 7.2.1 Art. 43: « all untoward and unintended responses to an investigational medicinal product related to any dose administered. »; EudraLex Volume 10 CT-3 Art. 44 provides further specification: « The definition covers also medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of the product »

Rulings for the reporting of suspected unexpected serious adverse drug reaction (SUSAR) use a more restrictive definition of causality:

• ICH E2A Section 3.A.1: « All cases judged by either the reporting health care professional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs  … The expression “reasonable causal relationship” is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship »
• EudraLex Volume 10 CT-3 Art. 45: « 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 »

Accordingly, there is an essential difference between causality rules for ADR (“causal relationship cannot be excluded” i.e. any category other than unrelated) and those for SUSAR to be reported in expedited fashion (“there are facts (evidence) to suggest a causal relationship”). In consequence, this might mean that not every ADR that is serious and unexpected is to be considered a SUSAR for expedited reporting.
This creates a grey area, which may cause over-reporting to avoid being QC’ed as ‘non-compliant’.

{25.Apr.2018 | ACPS-CdM}

In a blinded study, management (including reporting) of an SAE does not require unblinding. Unblinding is only indicated if the best medical management of the event requires knowing the identity of the IMP to which the subject was exposed (as in the case of a specific ‘antidote’ or ‘antagonist’). However, the identity of the IMP needs to be included in the SAE-report once unblinded.

Fur SUSAR, the need for (conditional) unblinding is detailed in EudraLex Volume 10 CT-3 Section 7.11.1 Art. 111-117. These provisions imply:
Art. 111: SUSAR-reporting to the EVCTM, competent authorities and ethics committees should be unblinded;
Art. 112-113: reporting to the investigators should be kept blinded unless unblinding was necessary for the safety of the patient,
Art. 114: whereas the SUSAR-information should be kept conditionally blinded within the sponsor’s organization (yes: PV-staff responsible for reporting of SUSAR; no: other staff involved in the study).

In extension thereof, EudraLex Volume 10 CT-3 Art. 115 and the Clinical Trial Regulation Annex III Section 2.5 Item 21 regulate an important exemption to the rule that any fatal or life-threatening SUSAR is subject to mandatory unblinding and expedited reporting: « … However, for clinical trials carried out in high morbidity or high mortality disease, where efficacy end-points could also be SUSARs or when mortality or another ‘serious’ outcome, that may potentially be reported as a SUSAR, is the efficacy end-point in a clinical trial, the integrity of the clinical trial may be compromised if the blind is systematically broken. Under these and similar circumstances, the sponsor shall highlight in the protocol which serious events are to be treated as disease-related and are not subject to systematic unblinding and expedited reporting. »

Originally, the EVCTM did not provide for reporting of SUSAR related to blinded IMP-IDs including placebo; in the meantime, it does (see EMEA/H/20665/ 04 (R2) “Note for Guidance EudraVigilance Human – Processing of Safety Messages and Individual Case Safety Reports (ICSRs)” Section 9 – Oct. 2010).

In consequence, it is possible and might be reasonable and desirable to report SUSAR on-trial without unblinding; however, such reports should be updated with the IMP’s ID once the study is unblinded.
It is advisable that in all other reporting (direct reporting to CA, reporting to ECs and investigators), a specific statement is included that specifies whether and why the IMP-ID is not disclosed (on-trial).