Understanding SUSAR (Suspected Unexpected Serious Adverse Reaction) and its Reporting in Clinical Trials

In clinical trials and pharmacovigilance, monitoring and reporting adverse events are of utmost importance to ensure patient safety and the accurate evaluation of investigational drugs or medical interventions. Among the various types of adverse events, one crucial category is the SUSAR (Suspected Unexpected Serious Adverse Reaction). As a follow up to my last blog on TEAE/TRAE/SAE/SAR definitions, this article gives an overview of what SUSARs are, how they are identified, and the process of reporting them during clinical trials.

What is a SUSAR?

A SUSAR (Suspected Unexpected Serious Adverse Reaction) refers to an adverse event in a clinical trial that meets three specific criteria:

1. Suspected: The event is suspected to be caused by the investigational product, but its causal relationship has not been definitively established.

   
   

2. Unexpected: The event is not consistent with the known safety profile of the investigational product based on available data and information.

   
   

3. Serious: The event results in one or more of the following outcomes: death, life-threatening situations, hospitalization or prolongation of hospitalization, significant disability or impairment, or congenital anomaly/birth defect.

Identifying SUSARs:

During a clinical trial, investigators and sponsors carefully monitor all adverse events reported by trial participants. If an adverse event meets the criteria for seriousness, it is designated as a Serious Adverse Event (SAE). Next, the clinical trial data and safety monitoring board or safety committee assess whether the SAE is "related" and therefore an SAR and if it is "unexpected" based on the known safety profile of the investigational product.

An SAE determined to be an SAR, or Serious Adverse Reaction, is a serious unexpected event that may be related to the investigational medicinal product (IMP). The term "unexpected" refers to the fact that the event was not previously observed in clinical trials or known to be associated with the IMP from other sources.

If the SAE is deemed "unexpected," meaning it is not consistent with the known safety information, it is classified as a SUSAR. This determination is made through a rigorous process of reviewing available data from the trial and other relevant sources such as the Reference Safety Information in the Investigator's Brochure.

Reference Safety Information:

The Reference Safety Information (RSI) is a document that provides information about the known safety profile of an investigational medicinal product (IMP). It is used by sponsors and investigators to assess the expectedness of serious adverse reactions (SARs) that occur in clinical trials.

The RSI includes information about the following:

• The known safety profile of the IMP, including the frequency, severity, and reversibility of adverse reactions.
• The expectedness of SARs, based on the known safety profile of the IMP and the patient population being studied.
• The reporting criteria for SUSARs, including the severity, timing, and causality of the adverse reaction.

The RSI is used to determine whether a SAR is unexpected and therefore warrants reporting as a SUSAR. If the SAR is not included in the RSI, or if it is included in the RSI but is considered unexpected, then it must be reported as a SUSAR.

SUSAR reporting is an important part of the safety monitoring of clinical trials. By reporting SUSARs, sponsors and investigators can help to identify and mitigate risks to patients.

Reporting SUSARs:

The reporting of SUSARs is subject to strict timelines and regulations to ensure timely evaluation and response to potential safety concerns. Reporting requirements for SUSARs are outlined in international guidelines and regulations, such as the International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and the European Medicines Agency (EMA) regulations.

Key steps in reporting SUSARs include:

Expedited Reporting: Once identified, SUSARs must be reported to the relevant regulatory authorities and ethics committees within specific timelines, typically within 7 to 15 days, depending on the severity of the event.

• Fatal or Life-threatening SUSARs need to be reported within 7 calendar days
• All other SUSARs need to be reported within 15 calendar days

1. Investigator and Sponsor Responsibilities: Investigators and sponsors collaborate in the reporting process. The investigator provides initial information, while the sponsor ensures all relevant details are included in the report.

   
   

2. Causality Assessment: The sponsor conducts a thorough causality assessment to determine the likelihood of the investigational product's involvement in the adverse event.

   
   

3. Follow-up Reporting: Follow-up reports may be required to provide additional information and updates on the SUSAR to regulatory authorities and ethics committees.

Conclusion:

SUSARs play a critical role in ensuring the safety and integrity of clinical trials. By identifying and reporting suspected unexpected serious adverse reactions promptly, investigators and sponsors can take necessary actions to protect trial participants and make well-informed decisions about the investigational product's safety profile. Adhering to stringent reporting timelines and regulatory requirements helps maintain transparency and accountability throughout the clinical trial process, ultimately contributing to the development of safe and effective medical interventions for patients in need.

Understanding the Differences Between TEAE, TRAE, SAE, and SAR in Clinical Trials

In clinical trials, adverse events are closely monitored to ensure the safety and efficacy of investigational drugs or medical interventions. Adverse events are undesirable and unintended medical occurrences that can happen during the course of a clinical trial. These events are categorized based on specific criteria to facilitate clear communication and reporting among investigators, sponsors, and regulatory authorities. In this article, I discuss the differences between four common types of adverse events: TEAE, TRAE, SAE, and SAR.

1. TEAE - Treatment-Emergent Adverse Event:

Treatment-Emergent Adverse Events (TEAEs) are adverse events that first appear or worsen in severity during the course of the clinical trial, regardless of whether they are related to the investigational treatment or not. TEAEs are critical to assess the safety profile of the drug under investigation. Investigators closely monitor and document any TEAEs observed in trial participants, providing data for further analysis and safety evaluation.

For example, if a participant in a clinical trial experiences a headache during the treatment period, and it was not present before starting the trial, this would be considered a treatment-emergent adverse event.

2. TRAE - Treatment-Related Adverse Event:

Treatment-Related Adverse Events (TRAEs) are adverse events that are considered to be caused or exacerbated by the investigational treatment. Distinguishing between TEAEs and TRAEs is essential in determining the drug's potential side effects and safety profile. Careful evaluation of the causal relationship between the treatment and the event is crucial for appropriate reporting and risk-benefit assessments.

For instance, if a trial participant develops a skin rash after starting the investigational drug, and it is determined to be a known side effect of the drug, this would be classified as a treatment-related adverse event.

3. SAE - Serious Adverse Event:

Serious Adverse Events (SAEs) are critical adverse events that result in one or more of the following outcomes:

• death, 
• life-threatening situations, 
• hospitalization or prolongation of hospitalization, 
• significant disability or impairment, 
• congenital anomaly/birth defect, or 
• any event that requires medical intervention to prevent any of the above outcomes

SAEs are closely monitored and reported to the regulatory authorities promptly, as they have the potential to impact the benefit-risk assessment of the investigational product significantly.

For example, if a clinical trial participant experiences a severe allergic reaction that requires immediate medical attention and hospitalization, this would be considered a serious adverse event.

4. SAR - Serious Adverse Reaction:

The term Serious Adverse Reaction (SAR) is often used in the context of pharmacovigilance and post-marketing surveillance of approved drugs. SAR refers to any adverse event for which there is a reasonable possibility that the drug under consideration caused the event. These events are carefully evaluated and assessed to determine the safety profile of the marketed product continually.

It's important to note that SARs are typically reported during the post-marketing phase when the drug is available to the general population, whereas TEAEs, TRAEs, and SAEs are primarily related to adverse events observed during clinical trials.

Conclusion:

In clinical trials and pharmacovigilance, clear and consistent categorization of adverse events is crucial to ensuring patient safety and the accurate evaluation of drug safety profiles. Understanding the differences between TEAEs, TRAEs, SAEs, and SARs aids investigators, sponsors, and regulatory authorities in their collective efforts to assess the risks and benefits of medical interventions, leading to better-informed decisions and improved patient care.

FDA Project Optimus: Reforming Dose Optimization in Oncology Drug Development

The FDA's Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology drug development. The current paradigm for dose selection is based on cytotoxic chemotherapeutics, which often leads to doses and schedules of molecularly targeted therapies that are inadequately characterized before initiating registration trials. This can result in patients receiving suboptimal doses of drugs, which can lead to decreased efficacy and increased toxicity.

Project Optimus aims to address this issue by promoting a new paradigm for dose optimization that emphasizes selection of a dose or doses that maximize not only the efficacy of a drug but the safety and tolerability as well. The FDA initiative intends to do this by educating, innovating, and collaborating with companies, academia, professional societies, international regulatory authorities, and patients.

Specific goals of Project Optimus include:

• Communicating expectations for dose-finding and dose optimization through guidance, workshops, and other public meetings.
• Developing and validating new approaches to dose optimization, such as Bayesian methods and adaptive designs.
• Promoting the use of real-world data to inform dose optimization decisions.
• Facilitating international collaboration on dose optimization research.

Project Optimus is a major undertaking, but it has the potential to significantly improve the way that oncology drugs are developed and approved. By ensuring that patients receive the right dose of the right drug, Project Optimus can help to improve the efficacy and safety of cancer treatment and ultimately save lives.

Some of the benefits of Project Optimus include:

• Increased likelihood of success in clinical trials.
• Reduced risk of toxicity.
• Improved efficacy.
• Increased quality of life for patients.
• Faster time to market for new drugs.

To use Project Optimus for your drug dose optimization plan, you will need to:

1. Understand the dose-response relationship for your drug. This means understanding how the dose of the drug affects its efficacy and toxicity. You can do this by conducting preclinical studies and clinical trials.
2. Develop a dose optimization plan. This plan should include the following:
   • The target efficacy and safety endpoints for your drug.
   • The range of doses that you will evaluate in your clinical trials.
   • The methods that you will use to assess the efficacy and toxicity of your drug at different doses.
3. Conduct clinical trials to evaluate the dose-response relationship for your drug. These trials should be designed to answer the following questions:
   • What is the optimal dose of your drug for efficacy?
   • What is the optimal dose of your drug for safety?
   • What is the relationship between dose and toxicity?
4. Analyze the data from your clinical trials to determine the optimal dose of your drug. This analysis should take into account the target efficacy and safety endpoints, as well as the results of your preclinical studies.

Here are some additional resources that you may find helpful:

• FDA Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
• Guidance for Industry: Dose Optimization in Oncology: https://www.fda.gov/media/144650/download
• Project Optimus Toolkit: https://www.fda.gov/media/144651/download