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RGA6212 - Pre-Market SUSAR Reporting

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Introduction

The reporting of incidents is crucial for identifying potential risks to subjects. Adverse

event reporting and monitoring procedures should be detailed in each clinical research protocol.

In addition, safeguards must be in place to provide adequate treatment for participants who have

unpleasant and unanticipated manifestations due to taking part in medical research. Details on

the investigator's and sponsor's roles in collecting, reviewing, and reporting adverse event data to

each other, the appropriate regulating IRBs, and the FDA should also be included in the protocol

(FDA). All adverse reactions the researcher noticed during a medical investigation and any

adverse events identified by a subject at any time should be included in the patient's assessment

documentation. Furthermore, each research participant should ask about adverse events at each

appointment. No matter how serious, these incidents all get recorded in the drug or device's

safety database.

As such, the FDA's ability to evaluate safety information effectively is hampered by

submitting many reports of isolated adverse events that fail to provide sufficient data or meet the

agency's reporting requirements. Overall, this hinders rather than improves the FDA's capacity to

safeguard human subjects in research. The severity, causal link to the treatment procedure,

response to the treatment procedure, result, predictability, and unexpectedness of an adverse

event should all be taken into account by researchers when documenting it. According to the

level of intensity experienced by the subject, the researcher may classify the unfavourable event

as mild, moderate, or severe. The difference between the severity and the extent of an adverse

occurrence should also be considered. A severe response is not always a dangerous reaction

since severity is a measurement of intensity. The researcher should note the severity of the side

effect and their correlation with the study substance. These criteria aid the sponsor in deciding
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whether the occurrence should be notified to the FDA and, if so, at what level of severity.

Reporting major adverse events to the IRB and regulatory agency should be hastened following

domestic and global requirements.

Therefore, to assist new colleagues in better grasping SUSAR reporting requirements,

this document highlights the FDA and ICH specifications of SUSAR reporting, describes the

safety profile of ITCA-650 and gives an in-depth study of 3 ITCA-650 adverse occurrences.

Description of FDA and ICH descriptions of SUSAR reporting

Sponsors of medical studies are obligated to provide safety reporting of specific adverse

incidents that happen throughout their studies so that health authorities can supervise the safety

of experimental treatments. Suspected Unexpected Serious Adverse Reaction (SUSAR) refers to

an undesirable event in a clinical study participant and is deemed by the sponsor and research

investigator to have a plausible causal link with the test substance (FDA, 2022). Such responses

should be reported immediately to health officials.

Therefore, an SAE is identified as an adverse and unforeseen reaction to a test substance

that is not enumerated in the pertinent product documentation and fulfils one of the preceding

serious metrics: consequences in death, threatens life, requires hospitalization or continuation of

existing hospitalization, causes enduring or substantial impairment or incapability, or is a

congenital abnormality or genetic disorder (FDA, 2022).

On the other hand, any unfavourable medical event in a  clinical trial participant after

receiving a pharmaceutical product but without a clear causal link to this therapy is referred to as

an adverse event (AE) (FDA, 2022). As such, it is crucial to remember that severity is not the

same as seriousness. Seriousness acts as a framework for determining regulatory reporting

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standards, whereas severity is predicated on patient/event results or action criteria often linked

with incidents that constitute a risk to a patient's life or functionality (FDA, 2022). In this

context, the causal relationship between a particular series of events is referred to as a casualty

(FDA, 2022). Moreover, serious Adverse Events can result in physical harm, psychological

distress, or even death. Allergic bronchospasm, a dangerous respiratory issue needing acute

medical treatment, illustrates an adverse occurrence (FDA, 2022).

Therefore, all significant and unexpected adverse drug reactions (ADRs) must be

reported quickly following International Council for Harmonization (ICH) guidelines (EMEA,

2006). Without regard to intent or methodology, this includes data from both unprompted reports

and clinical/epidemiological studies (EMEA, 2006). This includes incidents not initially reported

to the maker or sponsor (such as those documented in ADR registers created by regulatory

authorities or in media) (EMEA, 2006). Any information shared with the public should always

indicate where it came from (research, unexpected, or other).

Example of Adverse Event

A middle-aged guy was experiencing a rectal haemorrhage. The individual's doctor

performed a restricted sigmoidoscopy, which came up negative (PSNet, 2019). The patient's

rectal haemorrhage persisted, but the doctor reassured them (PSNet, 2019). He was taken to a

medical facility for assessment 22 months later following a 14-kg (30-lb) weight reduction

(PSNet, 2019). He was diagnosed with colon cancer that had spread to his liver. The doctors who

analyzed his medical records concluded that a competent diagnostic treatment may have detected

cancer while it was still treatable. The doctors blamed the advanced sickness on poor medical

treatment (PSNet, 2019). The event was deemed adverse (PSNet, 2019).
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Description of Safety Profile of ICTA-650

ITCA 650 is an osmotic mini-pump embedded underneath the skin to offer uninterrupted

subcutaneous transmission of exenatide (Intercia Therapeautic Inc, 2017). Proteins, peptides,

antibody fragments, and other extremely powerful biomolecules can be stabilized at or above

sentient body temperatures for up to three years with the help of this conveyance (Intercia

Therapeautic Inc, 2017). The ITCA 650 device administers exenatide, a GLP-1 receptor agonist

that enhances glucose homeostasis by acting on the kidneys, muscles, brain, and pancreas

(Intercia Therapeautic Inc, 2017).

ITCA 650 has been through four worldwide phases and three medical trials. It is

currently in its third clinical phase. In this phase, the researchers contrast the efficacy and safety

of therapeutic intervention against the available medical regimens. This is because, at this stage,

the doctors are still gauging which intervention works best; hence often pick participants

randomly to get a control sample and another study sample put on the new medical procedure

being studied. Afterwards, clinical trial data is transmitted to the FDA (or other regulating

organizations worldwide) for assessment and clearance following successful Phase 3 trials. To

decide whether a product under examination should be offered to consumers, the FDA examines

all the data from the three rounds of clinical studies; this is the preceding phase for ICTA-650.

According to non-clinical safety data from 30 studies on animals tested with

hyperglycemia, glucose levels were significantly lowered when ICTA 650 was given

consistently (Intercia Therapeautic Inc, 2017). The test population also reduced their food intake

and lost weight. Furthermore, mild reversible inflammations were witnessed in the study

subjects.
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Furthermore, in consideration of clinical safety data, among the adverse effects reported

in clinical trials were nausea, vomiting, diarrhoea, hypoglycemia, thyroid cancer, pancreatitis,

and pancreatic cancer. In addition, as predicted, side effects, hypersensitivity and acute renal

failure were identified. Clinical safety data notes that the ITCA 650 all dosages therapy group

had an increased prevalence of nausea (22.9% vs 4.0%), vomiting (15.0% vs 1.2%), and

diarrhoea (8.8% vs 3.9%) than the aggregated ITCA mock control cohort (Intercia Therapeautic

Inc, 2017). Therefore, the most prominent Gastrointestinal (GI)-related AEs expected with

ICTA-650 were nausea, vomiting, and diarrhoea (Intercia Therapeautic Inc, 2017).

Analysis of 3 ITCA-650 safety events

Case Study One

For this case study, a 55-year-old woman suffering from hypoglycemia for 11 years

experiences a minor episode after ten days of treatment. After a brief hospitalization, she is

discharged, and her blood sugar level is closely monitored. Hypoglycemia is the adverse effect in

this scenario. Minor is the severity of a condition. This is because Minor adverse effects refer to

real but lesser-magnitude effects. As such, a minor event results in mild or transient discomfort

that does not require intervention or treatment; does not limit or interfere with daily activities, as

evidenced by the patient's minor adverse effect. Moreover, according to the investigator's

brochure, this type of reaction was anticipated because the causality was related (Intercia

Therapeautic Inc, 2017). Since this is a non-serious adverse event, a non-expedited form of

reporting is most appropriate, as non-serious adverse reactions, whether expected or not, are

typically not subject to expedited reporting.

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Case Study Two

The second case study involves a 68-year-old man who experiences chest pains four

months after beginning treatment. Following treatment, the pain vanishes. Shortly after that,

however, the pain returns, and further analysis reveals that the patient belongs to the active

treatment cohort; consequently, they are removed from the study. This exclusion occurs

following a patient's myocardial infarction and three days of hospitalization. In this case study,

the adverse event considered severe is myocardial infarction. This condition meets the severe

criterion, as a condition is considered severe when significant symptoms necessitate

hospitalization, invasive intervention, transfusion, or elective radiological intervention (FDA,

2022). According to the case study, the patient was hospitalized for three days and thus deemed

very ill. The fact that this adverse occurrence was unanticipated necessitates both accelerated and

yearly DSUR/IND reporting (FDA, 2022). All significant and unexpected adverse drug reactions

(ADRs) are subject to accelerated reporting.

Case Study Three

This case study focuses on a 65-year-old lady suffering from abdominal pain due to type

II diabetes. The discomfort began 48 hours after the gadget was implanted in their body and

lingered for another 24 hours. As the surgery did not need hospitalization, the gadget was

withdrawn from the body, and the patient was released. However, after a thorough inspection,

the doctor could not identify any defects in the gadget, so he returned it to the manufacturer for

additional investigation. In addition, the patient healed adequately and experienced no more

discomfort once the gadget was withdrawn from their body. The extreme unfavourable

consequences in this circumstance include a wound and abdominal pain. These unfavourable
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consequences were unanticipated; the causation is linked to the clinical trial (FDA, 2022). In

addition, the adverse effects are regarded as severe owing to the intensity of the incident and the

required intervention. As a result, expedited and DSUR/IND annual reports are optimal for this

scenario.

Conclusion

It is the primary goal of the SUSARs to safeguard patients, but they also serve to update

researchers on relevant changes, guarantee adherence to rules, and safeguard the reliability of

studies. Further, clinical reports give the historical data-driven information required to improve

efficiency, lessen the occurrence of medical complications, and meet productivity goals. Due to

the need to make sure the planned regimen meets all requirements before being authorized,

reporting is crucial. This is beneficial as it is key to avoiding catastrophes resulting from a

clinical error.

For ITCA 650, for instance, the therapeutic approach aims to reduce glucose, HbA1c, and

weight by starting with medically appropriate and well-tolerated dosage and gradually increasing

it. So far, studies using ITCA 650 have shown that constant delivery of exenatide through a

subdermally inserted ITCA 650 osmotic mini-pump is safe, effective, and well tolerated for

treating diabetes, as measured by reductions in haemoglobin A1c, fasting glucose, and

postprandial glucose. To reach this stage, numerous reports have been filed and submitted to the

relevant regulatory bodies to mitigate the ADR that can arise from the intervention. As the case

study demonstrates, regulatory agencies rely on clinical reports like these to establish whether or

not a clinical intervention or treatment regimen is safe hence avoiding resulting catastrophes.
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References

EMEA. (2006). ICH Topic E 2 A: Clinical Safety Data Management: Definitions and Standards

for Expedited Reporting. London: European Medicines Agency.

FDA. (2022, July 20). CFR - Code of Federal Regulations Title 21. Retrieved from FDA, U.S.

Food and Drug Administration:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32

Intercia Therapeautic Inc. (2017). ITCA 650 (Exenatide in Osmotic Mini-Pump): Investigator's

Brochure.