Safety reporting during a clinical trial
Safety information about a trial participant moves along a chain: the investigator assesses it and reports it to the sponsor, and the sponsor evaluates it and reports onward to the regulatory authorities, the ethics committees and the investigators, each step within time limits that the protocol and the applicable requirements set.
Definitions
An adverse event is any unfavourable medical occurrence in a trial participant administered the investigational product, and it does not necessarily have a causal relationship with the treatment.
An adverse drug reaction has one definition for pre-approval experience and another for marketed products. In pre-approval experience with a new product or its new usages, particularly as the therapeutic dose may not be established, it is an unfavourable and unintended response, such as a sign including a laboratory result, a symptom or a disease, related to any dose of a medicinal product, where a causal relationship between the product and the event is a reasonable possibility. For marketed products it is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or for modifying physiological function. A practitioner's introductory account defines an adverse drug reaction more simply, as one caused by the study drug.
The reference safety information contains a cumulative list of the adverse drug reactions expected for the investigational product administered to participants in a clinical trial, and it is included in the investigator's brochure or in alternative documents according to applicable requirements. The level of certainty about the relatedness of an adverse drug reaction to the product varies, and where a reaction is suspected to be product-related with a high level of certainty it should be included in the reference safety information and/or the investigator's brochure. ICH E2F, the guideline on the development safety update report, gives more information on the reference safety information.
"Serious" has a technical meaning in clinical research. A serious adverse event is any unfavourable medical occurrence considered serious at any dose if it results in death, is life-threatening, requires inpatient hospitalisation or prolongs an existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. An important medical event that may not be immediately life-threatening or result in death or hospitalisation, but that may jeopardise the participant or require intervention to prevent serious outcomes, should generally also be considered serious.
Not every serious adverse event indicates a potential problem with the drug being investigated. An overnight hospital stay for a sprained ankle, for example, is categorised as serious because of the hospitalisation, although it is unlikely to be associated with the study drug and may not be a cause of concern for the safety of other participants in the trial.
A suspected unexpected serious adverse reaction is an adverse reaction that meets three criteria: suspected, meaning there is a reasonable possibility that the drug caused the reaction; unexpected, meaning the nature or severity is not consistent with the applicable product information, such as the investigator's brochure or an alternative document according to applicable requirements; and serious, as defined above. "Unexpected" means the event is not an already known side effect of the drug, and established or known side effects are listed either in the investigator's brochure or in the approved label. The term "suspected" reflects that, while a drug is still being investigated, it is unlikely to be known for certain whether a particular adverse event is an adverse reaction.
Planning the collection and management of safety information
The management of safety information is an essential part of clinical trials, protecting participants' safety through early detection and management of potential adverse drug reactions. To protect participants, it is important that safety data are collected and rapidly processed on an ongoing basis.
The approach to safety management, including any mitigating actions to safeguard participant safety, and the approach to reporting should be described in the protocol or protocol-related documents such as the safety management plan, taking into account the methodologies the trial uses. Where appropriate, consideration should be given to ICH E19's selective approach to safety data collection in specific late-stage pre-approval or post-approval clinical trials.
Where a trial has decentralised or pragmatic elements, safety information may be collected in several ways and from several sources, for example remote visits, digital health technologies, electronic health records, in-person visits, or a combination. The sponsor should then ensure that appropriate processes and procedures are in place to make that information accessible to the investigator in a timely manner according to the protocol. The information should reach the investigator in a way that lets them make decisions on the participant's care and ensures the participant's safety. Where digital health technologies collect the data, for example, the sponsor should ensure the information reaches the investigator in a form that is relevant, meaningful and manageable, giving an effective overview of the participant's health status and enabling timely, appropriate medical decisions.
Assessment and reporting by the investigator
For the safety monitoring of individual participants, the investigator should review and assess information on participants' health status across the sources of safety-related information. Safety information generated from home nursing, remote visits and digital health technologies, for example, should be provided to the investigator in a way that lets them make decisions on the participant's care and ensures the participant's safety.
Adverse events and/or abnormal test results required for safety evaluations, as the protocol sets them out, should be reported to the sponsor according to the reporting requirements and within the time periods the protocol specifies. Unfavourable medical events occurring before the product is administered, during screening for example, should be considered and reported to the sponsor if the protocol requires it.
All serious adverse events should be reported to the sponsor immediately after the investigator reasonably becomes aware of them, and the investigator should include an assessment of causality. In accordance with applicable requirements the protocol may identify serious events that do not require immediate reporting, such as deaths or other events that are endpoints. Subsequent information should be submitted as a follow-up report as necessary. For reported deaths, the investigator should supply the sponsor, the ethics committee and, where applicable, the regulatory authority with any additional requested information, such as autopsy reports and terminal medical reports, when it becomes available.
A 2018 practitioner account states that the investigator is required by law to report certain kinds of adverse event to the sponsor without delay, within 24 hours of becoming aware of them. It calls this expedited reporting and states that it always applies to serious events.
The investigator may delegate safety reporting activities to qualified site staff but retains overall responsibility for the safety of the participants under their responsibility and for compliance with the reporting requirements.
Sponsor review of safety information
The sponsor is responsible for the ongoing safety evaluation of the investigational product. The investigator's brochure or, where applicable, current scientific information such as a basic product information brochure forms the basis of safety assessment and reporting for the trial.
The sponsor should aggregate, as appropriate, and review relevant safety information in a timely manner, including any reported unfavourable medical events occurring in participants before product administration, during screening for example. That review may result in updating the protocol, the investigator's brochure, the informed consent materials and related documents. The sponsor should also review available emerging safety information to assess whether there is new data that may affect a participant's willingness to continue, affect the conduct of the trial, or alter an approval or favourable opinion of the ethics committee and/or the regulatory authority, as applicable. Any information of that nature should be communicated to participants, the investigator, the committee and the authorities, as applicable, in a timely manner.
Reporting by the sponsor
The sponsor should submit safety updates and periodic reports, including changes to the investigator's brochure, to the regulatory authorities as applicable requirements demand. It should expedite the reporting of all suspected unexpected serious adverse reactions to the regulatory authorities in accordance with applicable requirements and with ICH E2A. According to a 2018 practitioner account, the sponsor must report such a reaction to the regulatory authorities, such as the FDA, within 15 days, or within 7 days if the event is life-threatening or fatal.
Safety reporting to the regulatory authorities should assess the expectedness of the reaction against the applicable product information, such as the reference safety information in the investigator's brochure or alternative documents, in accordance with applicable requirements. The reference safety information in the brochure provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions. Its list of adverse reactions should be used to determine whether a suspected serious adverse reaction is expected and so whether its reporting needs to be expedited in accordance with applicable requirements.
Suspected unexpected serious adverse reactions should be reported to investigators, institutions and ethics committees in a manner reflecting the urgency of the action required, taking into account the evolving knowledge of the product's safety profile and in accordance with applicable requirements. In some regions periodic reporting of line listings with an overall safety assessment may be appropriate. Urgent safety issues requiring immediate attention or action should be reported to the ethics committee and/or the regulatory authorities and to the investigators without undue delay and in accordance with applicable requirements.
Alternative arrangements for safety reporting to authorities, committees and investigators, and for reporting by investigators to the sponsor, should be prospectively agreed with the regulatory authorities and, if applicable, the ethics committee, and described in the protocol. One example is serious adverse events considered efficacy or safety endpoints, which would not be subject to unblinding and expedited reporting. ICH E19 sets out a selective approach to safety data collection in specific late-stage pre-approval or post-approval clinical trials.
Immediate hazards
The sponsor should take prompt action to address immediate hazards to participants, determine the causes of the hazard and take appropriate remedial action on that basis. It should consider whether the protocol requires amendment in response. The information on the immediate hazard, if required, and any subsequent amendment should be submitted to the ethics committee and/or the regulatory authorities by the investigator, the institution or the sponsor, in accordance with applicable requirements.