What is suspected unexpected Serious Adverse Event?

A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is both suspected to be caused by an investigational medicinal product and unexpected. SUSARs require expedited reporting so that regulatory authorities can take appropriate safety measures to protect clinical trial participants.

What are the criteria for a SUSAR?

For an adverse event to be classified as a SUSAR, it must meet all of the following criteria:

• Suspected – There is a reasonable possibility that the adverse reaction may have been caused by the investigational medicinal product. This is determined by the investigator based on factors such as timing of the event relative to drug exposure, known pharmacology, presence of other possible causes, etc.
• Unexpected – The adverse reaction is not consistent with the applicable product information (e.g. Investigator’s Brochure for an unapproved investigational product).
• Serious – The adverse event meets one or more of the following outcomes:
  • Death
  • Life-threatening (places the subject at immediate risk of death)
  • Inpatient hospitalization or prolongation of existing hospitalization
  • Persistent or significant disability/incapacity
  • Congenital anomaly/birth defect
  • Other medically important event (based on medical judgement)

All three criteria must be met for an adverse event to qualify as a SUSAR. Just meeting one or two criteria is insufficient.

What types of events should be reported as SUSARs?

Any adverse event meeting the SUSAR criteria should be reported, regardless of the severity or expectedness. This includes common adverse reactions if they occur in an unexpected manner. Examples of potential SUSARs include:

• Known side effects that are more frequent or severe than expected based on the Investigator’s Brochure
• New adverse reactions not previously associated with the investigational product
• Adverse reactions with an unexpected outcome (e.g. hospitalization for a typically mild reaction)
• Reactions due to incorrect use of the product such as overdose, medication error, or misuse
• Reactions due to interactions with concomitant medications

The investigator at each clinical site is responsible for determining if an adverse event meets the criteria for a SUSAR based on the details of the specific case.

What is the process for reporting SUSARs?

SUSARs require expedited reporting within mandated timeframes based on the seriousness criteria met:

• Fatal or life-threatening SUSARs – Must be reported to regulatory authorities and investigators within 7 calendar days after first knowledge by the sponsor.
• All other SUSARs – Must be reported within 15 calendar days.

The reporting timeline begins when the sponsor is first made aware of the event. Once a SUSAR is identified:

1. The investigator reports it to the sponsor and ethics committee per the study protocol.
2. The sponsor confirms it meets the SUSAR criteria.
3. The sponsor reports it to regulatory authorities and investigators in all countries where the investigational product is being studied.
4. Investigators submit follow-up reports with additional details to the sponsor and ethics committee.
5. The sponsor forwards follow-up data to regulators.

Electronic reporting systems are usually utilized to facilitate rapid submission and tracking. Sponsors must document that appropriate SUSAR reporting procedures are followed.

What information must be included in a SUSAR report?

Initial SUSAR reports must include the following information:

• Identifier code for the clinical trial and investigational product
• Report type (initial/follow-up)
• Reporter information (sponsor/investigator)
• Patient details including initials, age, gender
• Adverse event description, seriousness criteria met, start/stop dates, treatment details
• Investigator’s causality assessment and rationale
• Sponsor’s evaluation of expectedness and relatedness to investigational product

Follow-up reports should provide additional details as they become available, such as final outcome, alternative causes, clinical course, and investigator comments.

How are SUSARs tracked and analyzed?

Sponsors are responsible for establishing a pharmacovigilance system to track and analyze SUSAR reports across all clinical trials. This includes:

• Maintaining a safety database of all SUSARs
• Reviewing incoming SUSARs for trends or new safety signals
• Evaluating if any safety actions need to be taken, such as changes to the Investigator’s Brochure, protocol amendments, or placing the trial on hold
• Regularly analyzing the safety database to identify any clustering of SUSARs or increased event frequency
• Submitting periodic safety reports to regulators summarizing SUSARs and overall safety profile

Data mining techniques may be used to systematically analyze the safety data and detect associations between adverse events and patient characteristics or treatment factors.

When is an expedited safety report required?

In addition to individual SUSAR reports, an expedited safety report must be submitted to regulators if any of the following situations occur:

• Single SUSAR is deemed sufficient to consider changes to the investigational product’s use or conduct of the trial
• Accumulation of SUSARs or other findings suggest the product is not reasonably safe
• New animal data demonstrates significant risk to humans
• Any clinically important increase in the rate of occurrence of SUSARs
• Major safety findings from a newly completed non-clinical study (e.g. carcinogenicity study)

These expedited reports summarize the relevant safety data and provide an analysis supporting the safety concern. The recommended regulatory actions or amendments to the risk management plan are also outlined.

How are investigators informed about SUSARs?

Investigators at all trial sites must be promptly informed of SUSAR reports relevant to the investigational product they are studying. This is usually accomplished via:

• Safety notification letters with a summary of the SUSAR
• Updates to the Investigator’s Brochure
• Protocol amendments
• Revised subject information sheets

Investigators must share this information with their ethics committee and use it to re-assess the risks and benefits for study participants. Any additional measures to protect subject safety should be implemented.

When does SUSAR reporting end?

SUSAR reporting continues throughout the entire clinical trial period, from enrollment of the first subject until the global end of the trial. Once the clinical trial has officially ended in all countries:

• Individual SUSAR reporting stops
• Sponsors must continue to monitor any ongoing adverse events until resolution
• A summary safety report is submitted to regulators within 90-360 days of trial completion
• Post-marketing pharmacovigilance begins if the product is approved

SUSAR reporting provides critical safety oversight during clinical trials. Proper identification and expedited reporting of SUSARs allows risks to be quickly addressed and trial participants to be protected.

What are some real-world examples of SUSARs?

Here are some examples of adverse events that were reported as SUSARs in past clinical trials:

Severe phototoxic skin reaction

• Occurred in phase 2 trial of an investigational kinase inhibitor for cancer
• Patient experienced severe sunburn-like rash on sun-exposed skin after taking study medication and spending time outside
• Reaction was unexpected and met seriousness criteria (hospitalization)
• Reported as a SUSAR which led to a warning about phototoxicity being added to the Investigator’s Brochure

Acute kidney injury

• Occurred in phase 3 trial of an antibiotic for urinary tract infections
• Elderly patient developed sudden decrease in kidney function after 5 days of treatment with study drug
• Investigator suspected causality due to timing and lack of alternative explanation
• Reported as a life-threatening SUSAR and led to closer monitoring of renal function

Anaphylactic reaction

• Occurred in phase 1 trial of a monoclonal antibody
• Subject experienced lip swelling, rash, low blood pressure, and shortness of breath within minutes of infusion
• Required emergency medications and hospitalization
• Reported as a SUSAR although allergic reactions were previously documented
• Resulted in slower infusion rates and closer monitoring in subsequent cohorts

Conclusion

SUSAR reporting is a crucial pharmacovigilance obligation for clinical trial sponsors. Identifying, evaluating, and submitting SUSARs in a timely manner allows ongoing safety review and protection of study subjects. Comprehensive tracking and analysis of SUSARs may also uncover important safety signals that influence the future development or prescribing of the investigational product.