Administrative information
Open Science
Introduction
Methods: Patient and public involvement, trial design
Methods: Participants, interventions, and outcomes
Methods: Assignment of interventions
Methods: Data collection, management, and analysis
Methods: Monitoring
Ethics
Harms
Item 17: How harms are defined and will be assessed (e.g., systematically, non-systematically)
Example
“Those administering the study products, all other trial staff collecting safety and immunogenicity endpoints, and the participants and parents will be blind …
​DEFINITIONS​
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Adverse event (AE)
Based on ICH-GCP E6 (R2), an AE in this trial is defined as any untoward medical occurrence in a participant administered a study product which does not necessarily have a causal relationship with the study product itself. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the administration of the study product whether related to the study product or not. Symptoms, signs or conditions present at screening (visit 0) which do not change are not AE and will be recorded as part of the screening procedures. Any subsequent change in the severity of a symptom, sign or condition following screening will be recorded as AE.
Serious adverse event
An AE is defined as serious if it:
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Results in death
Any deaths will be reported as grade 5 severity
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Is life threatening
The term life-threatening in the definition of serious 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 was more severe.
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Requires inpatient hospitalization or prolongation of existing hospitalization
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Results in persistent or significant disability/incapacity
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Is a congenital anomaly/birth defect
Important medical event
Important medical events that may not be immediately life threatening or result in death or hospitalization, but which may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition of serious should be reported in the same ways as serious adverse events.
Suspected unexpected serious adverse reaction
AE that are serious or are important medical events, that are judged to be related to study product administration, and that are unexpected based on the information contained in the reference safety information will be termed suspected unexpected serious adverse reactions (SUSARs)
SOLICITED ADVERSE EVENTS
The following solicited local and systemic adverse events will be collected and graded for severity based on the National Institutes of Health (NIH), Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric adverse events (version 2.1. Jul 2017):
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Adult local: pain, redness/erythema, swelling/induration, pruritus
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Toddler and infant local: pain, redness/erythema, swelling/induration
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Adult systemic: acute allergic reactions (day 0 only), axillary temperature, vomiting, diarrhoea, headache, fatigue, myalgia, arthralgia and rash
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Toddler and infant systemic: acute allergic reactions (day 0 only), axillary temperature, vomiting, diarrhoea, irritability, drowsiness, appetite and rash
Solicited AE will be recorded on the day of study product administration (visit 1 — day 0) by the study clinician and daily through home visits conducted by trained field workers between day 1 and day 13 post-study product administration. Any local and systemic AE ongoing after day 13 will be recorded by the study clinician as an unsolicited AE at the day 14 clinic visit (visit 3). Any grade 3 solicited AE identified during home visits will prompt an unscheduled clinic visit and review by a clinical study clinician on the same day or within 24 h at the latest.
Solicited AE data from home visits will be reviewed daily by a study clinician. In addition, home visits will be spot checked by senior members of the field team to ensure the quality and consistency of findings.
UNSOLICITED ADVERSE EVENTS
Any event fulfilling the definition of an AE, but which is not reported based on the definition of solicited local and systemic AE will be reported as unsolicited AE. When possible, collections of individual signs and symptoms will be reported as the underlying clinical syndrome. For example, gastroenteritis should be reported rather than diarrhoea, vomiting and fever. If an underlying clinical syndrome is not apparent, symptoms and signs will be reported individually. Unsolicited AE will be coded by preferred term (PT) and primary system, order, class (SOC) for reporting according to the latest online version of the MedDRA®.
CLASSIFICATION OF ADVERSE EVENTS
Severity
Solicited local and systemic AE as well as unsolicited AE will be graded for severity based on the NIH DAIDS Table for Grading the Severity of Adult and Pediatric AE (version 2.1. Jul 2017) or, if not included, based on the criteria set out in Table 5. The highest severity grade applicable at any point during an illness will ultimately be reported. Any AE which results in death will be defined as severity grade 5.
Causality
Other than solicited local reactions which, by definition, are related to study product administration, other AEs will be assessed for relatedness to the study vaccine by a study clinician.
The relatedness of a particular AE will be assessed based on clinical judgment considering the timing of the event in relation to study product administration, the nature of the event, the presence or absence of other illnesses or conditions to explain the event and relevant background history and concomitant medication use.
Based on these assessments, the relationship between a given AE and study product will be defined as:
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Related: There is a reasonable possibility of a causal relationship between the AE and the study product administered. The AE is more likely to be explained by the administration of the study product than by another cause.
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Not related: There is not a reasonable possibility of a causal relationship between the AE and the study product administered. The AE is more likely to be explained by another cause.
Given the double-dummy design, at the time of the initial unblinded assessment of an AE, it will not be possible to establish whether systemic AE is related to the MRV-MNP [measles and rubella vaccine microneedle patches] or MRV-SC.
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Expectedness
Expectedness, either ‘expected’ or ‘unexpected’, will be assessed for unsolicited related AE by the sponsor’s medical expert based on the latest Investigator’s Brochure for the MRV-MNP and summary of product characteristics (SmPC) for the SC injection. For systemic events, the SmPC will serve as the reference safety information for the purposes of assessing expectedness of any reactions to the MRV irrespective of administration methods. Therefore, any systemic reaction judged to be expected based on the SmPC for the MRV will also be defined as expected following MRV-MNP.
Outcome
The outcome of AE will be defined as resolved/recovered, resolved/recovered with sequelae, ongoing stable chronic condition, ongoing at end of the study visit, resulted in death and unknown.
Safety laboratory investigations
Screening (visit 0) and safety (visit 2 and visit 3 [adults only]) laboratory investigations will be performed in the MRCG CSD laboratories according to their Standard Operating Procedures (SOPs). The SOPs govern the processes of sample reception, sample processing and result reporting. The CSD biochemistry, haematology, microbiology and serology laboratories are all ISO15189 accredited and Good Clinical Laboratory Practice (GCLP) compliant.
All abnormal safety labs will be graded based on a locally appropriate grading scale and will be judged for clinical significance and relatedness. Abnormal safety labs will be repeated as clinically indicated”[273].
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Explanation
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Evaluation of harms plays a key role in monitoring the well-being of participants during a trial and in enabling appropriate management of adverse events. Documentation of trial-related adverse events also informs clinical practice and the conduct of ongoing and future studies. Use of the term “harms” is preferred over “safety” to better reflect the negative effects of interventions [274], although we recognise that regional and organisational practices vary in the terminology used.
An adverse event refers to an unwanted occurrence during the trial, which may or may not be causally related to the intervention or other aspects of trial participation [274, 275] This definition includes unfavourable changes in symptoms, signs, laboratory values, or health conditions. An adverse effect is a type of adverse event that is attributed to being caused by the intervention. In the context of clinical trials, it can be difficult to accurately attribute causation for an adverse event experienced by an individual participant [276].
How harms outcomes are assessed will impact the results obtained [277-280]. Harms outcomes can be either systematically assessed (i.e., solicited by active or targeted surveillance) or non-systematically assessed (i.e., unsolicited or spontaneous declaration; passive surveillance). To increase statistical power, harms outcomes are sometimes grouped in a composite outcome (e.g., cardiovascular events).
Specifying the methods of assessing, grouping, and analysing harms in the protocol helps to identify and deter the selective reporting of results in publications and registries [281, 282]. Substantial discrepancies have been observed between protocol-specified plans for harms data collection and reporting, and what is described in publications of completed trials [283].
The protocol should list the systematically and non-systematically assessed harms outcomes that will be collected, as well as their time points of assessment and overall surveillance time frame. It is important to state who will perform the assessment, coding, severity grading, and grouping, and whether those individuals will be blinded to the allocated trial group.
For each systematically assessed harms outcome, the information outlined in item 16 should be reported, including the outcome definition, instrument used (e.g., name of a validated questionnaire), analysis metric (e.g., final value), method of aggregation (e.g., proportion), and the time point of interest for analysis. The data collection methods should also be described as outlined in item 25a.
For non-systematically assessed harms outcomes, protocol authors should report how data will be collected (item 25a), including any standardised questions used to solicit information. It is important to describe the process for coding adverse events (e.g., using standardised terminology) and grading their severity, including the coding system (e.g., Medical Dictionary for Regulatory Activities) and severity grading system (e.g., Common Terminology Criteria for Adverse Events).
Harms outcomes are often grouped by seriousness, severity, body system, discontinuation of interventions due to harms, and causality attribution [277]. If aggregation of adverse events is planned, then protocol authors should define the grouping categories. If harms will be categorised as being causally related to the intervention or not, authors should describe the attribution methods, including who will make the causal attribution and whether they will be blinded to the assigned trial group [284].
If applicable, the protocol should address how important adverse events will be reported to relevant groups (e.g., sponsor, research ethics committee/institutional review board, data monitoring committee, regulatory agency), a process that is defined by local regulation [285]. Key considerations determining the need to report an adverse event to external groups include its severity, potential causality, and whether it represents an unexpected event.
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Summary of key elements to address​
For each systematically assessed harm (active/targeted surveillance):
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Definition and measurement (e.g., name of validated questionnaire)
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Where appropriate, the metrics, method of aggregation, and time point of interest for analysis
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Procedures for harms assessment , including:
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Who will do the assessment, and whether they will be blinded to the allocated trial group
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Assessment time points and overall time period for recording harms
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For each non-systematically assessed harm (passive surveillance):
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How data will be collected
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Assessment time points and overall time period for recording harms
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Process for coding each adverse event and grading its severity, including:
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Who will do the coding and severity grading, and whether they will be blinded to the allocated trial group
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Which coding and severity grading systems will be used, if any
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For grouping of harms by seriousness, severity, body system, discontinuation of intervention (due to harms), and causality:
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Definitions of grouping categories
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Who will do the grouping, and whether they will be blinded to the allocated trial group​
If relevant:
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Process of reporting important adverse events to applicable groups (e.g, sponsor, regulator, data monitoring committee)