An important aspect of PROMETRIKA’s work as a full-service CRO for sponsors is the monitoring and reporting of safety-related events during clinical trials. Our sponsor colleagues focus on drugs and biologics addressing rare diseases and other conditions that so far have proven difficult to treat. PROMETRIKA’s Safety and Pharmacovigilance activities are focused on accurate and timely drug safety reporting.

In June and September of 2021, FDA published two draft guidances focusing on drug safety reporting requirements and safety assessments for investigational products. The first is entitled “Sponsor Responsibilities – Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies” and the second, “Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices.” A later installment of this series will cover the investigator’s responsibilities. But first, I will discuss sponsor responsibilities by addressing notable components of the guidance, take-home messages, and FDA’s philosophy in developing the guidance.

The purpose of the sponsor-focused guidance is to help sponsors comply with the expedited drug safety reporting requirements for investigational drugs and biologics being studied under a US Investigational New Drug Application (IND), as well as the reporting requirements for bioavailability and bioequivalence studies, which are exempt from IND requirements. While IND safety reporting requirements apply to drugs and biologics, I will use the term drug as a reference to both.

The “Sponsor Responsibilities” guidance merges content from two previously issued guidances. Critical features are the determination of causality for the assessment of expedited reporting and, the most difficult part of ongoing safety review, the review of aggregate data. For the latter, the FDA is particularly helpful in providing concrete suggestions as to how sponsors can adequately address aggregate review. FDA acknowledges that this can be a difficult process requiring a multidisciplinary team where, in additional to the clinical study database, one needs a fully functional drug safety unit and an electronic system for storing, accessing and querying serious adverse event (SAE) reports and terms.

Much of the new information in the guidance includes recommendations regarding drug safety assessments and aggregate analyses in blinded studies, including recommended approaches to planned unblinding of safety data and implications for trial integrity. The guidance provides flexibility regarding review of aggregate safety information for IND safety reporting so that these can be tailored to the investigational agent and clinical trial program. It addresses the scope and methodology for aggregate analyses, which are part of ongoing safety surveillance plans (SSPs).

Front-and-center is the need for a systematic approach to the review of drug safety information, ideally in a written SSP. This plan should describe the processes and procedures for assessing SAEs and other important safety information in a development program. The plan generally describes a multidisciplinary approach, with clearly defined roles and responsibilities for the staff who have responsibility for reviewing, analyzing and making decisions regarding IND safety reporting. SAEs and other important safety information should be reviewed periodically as outlined in the plan. For blinded studies, there should be a clear description of conditions whereby unblinding may be considered necessary to accurately interpret the data, as well as provisions for maintaining trial integrity. The timing of regularly scheduled data reviews should be indicated in the plan, and the plan itself should be reviewed and updated, if necessary, at regular intervals.

For the purposes of drug safety reporting as required in the Code of Federal Regulations (21CFR312), an adverse reaction or suspected adverse reaction (SAR) is defined as one for which there is a reasonable possibility that the drug caused the AE. For the purposes of IND safety reporting, reasonable possibility means there is evidence to suggest a causal relationship between the drug and the AE. This is in contrast to the older criterion that a causal link cannot be ruled out. In most cases, this means that there has been more than one occurrence of the event, or an aggregate analysis of specific events observed in a clinical trial indicates that they occur more frequently in the treatment group than in a concurrent or historical control group. One exception to this is the single occurrence of an event that is uncommon and known to be strongly associated with drug exposure, such as Stevens-Johnson Syndrome. Additionally, one or more occurrences of an SAE that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug also meets the definition of an SAR.

According to the FDA requirements, it is the sponsor’s responsibility to determine causality of an event. While one routinely asks the investigator for a causality assessment, for the purposes of FDA safety reporting, the final responsibility of assessing causality belongs to the Sponsor. It should be noted that this is different from the ICH E2A guidance, which allows that the assessment can be that of either the investigator or Sponsor. For multinational studies, this may result in different expedited reporting requirements in different regions.

Other requirements include reporting findings that suggest a significant risk in ongoing or completed studies, pooled data from multiple studies, epidemiological studies, published and unpublished literature, and findings from animal or in vitro testing that may include carcinogenicity, mutagenicity, teratology, or significant organ toxicity at or near the expected human exposure.

We are all familiar with the requirement to report serious and unexpected suspected adverse reactions (SUSARs) in an expedited fashion. With each such report, it is also the responsibility of the sponsor to identify all IND safety reports previously submitted to FDA concerning a similar SAR and to analyze the significance of the new event in light of previous similar reports and other relevant information. This analysis needs to focus on all studies and post-marketing experience with the drug, not just the study in which the current event occurred. It is important to consider the size of the increase in rate of occurrence, as well as the consistency of occurrence across studies in determining the importance of the current and the related events.

Events that require aggregate analyses are a bit more complicated and FDA spends quite a bit of time describing these analyses in the guidance. In addition to concrete recommendations as to how this can be done, the rationale for these recommendations is also very informative. Events related to the underlying disease or condition under investigation, common in the population or known to occur with drugs administered as part of a background regimen, may be reported to sponsors as SAEs but are generally not the subject of expedited reporting. The purpose of the aggregate analysis is to look at each SAE and compare the incidence to a control or historical group to see if there is an increased incidence in the reporting of these events, which could be indicative of a causal relationship.

In the guidance, FDA provides suggestions on how to approach aggregate drug safety review. The first step is to generate a list of anticipated events (preferably using MedDRA terminology). These also include AEs of special interest (AESIs) and are usually based on potential safety signals in animal studies or on previous experience with the drug. It is important to monitor for these events at appropriate intervals, which may be based on specific dates or clinical trial enrollment. This aggregate analysis should be an integral part of the SSP and interpretation of differences requires clinical and statistical expertise. Generally, differences need to be large to conclude that there is an increased incidence of an event that warrants an expedited safety report. The same process needs to be in place to analyze known SARs to determine if there is a clinically significant increase of any given SAR above that in the reference safety information as this, too, will warrant an expedited safety report.

In a blinded study, the drug safety monitoring process should protect the integrity of blinding. This may require that the individuals involved in unblinded review of certain events be separate from study personnel or it may even involve the use of a Data Monitoring Committee. Internal personnel conducting unblinded safety reviews cannot participate in the conduct or analysis of the blinded trial or other trials with that drug. Appropriate procedural controls and processes should be prospectively specified in the SSP to prevent sponsor personnel involved in the conduct or analysis of the trial(s) from being unblinded to individual subjects’ treatment assignments.

Determining when the aggregate safety data provides evidence suggesting a causal relationship or a clinically significant increased incidence of a SUSAR is a complex judgement. For this reason, it is important that Sponsors have SSPs, and document the results and conclusions of these analyses. The process needs to be multifunctional with pharmacovigilance/drug safety, statistics, and medical personnel having critical roles in the analyses and recommendations. As FDA points out in the guidance, even statistically non-significant imbalances may be relevant and interpretation may require a broader evaluation.

FDA outlines two approaches to analyzing aggregate data in clinical investigations:

  1. Estimate and pre-specify the estimated background rate in the population and set an unblinding “trigger” rate based on the rate in the blinded data. If the rate is exceeded, an unblinded analysis by treatment group is conducted.
  2. Regularly analyze unblinded data on SAEs by treatment group to assess whether there is a meaningful increase in a particular event in the treatment group as compared to the control. While this approach does not require identifying predicted rates of events, it does require well planned and well-documented efforts to protect data integrity and making sure that the staff conducting these analyses are separate from staff involved in the clinical trials.

While individual cases are submitted to FDA on a MedWatch form, IND safety reports based on aggregate analyses must be submitted in the form of a narrative summary report, which should include a summary of the analysis of the individual cases, including the individual case identifiers, and identify previously submitted IND safety reports concerning a similar SAR. In addition, other safety-related information should be updated as appropriate (e.g., Investigator’s Brochure, informed consent form).

The time frame for submitting IND safety reports of more than one event or increases in rates of occurrences of serious suspected adverse events is no later than 15 days after the sponsor determines that it qualifies for reporting.

The guidance also provides details on bioavailability/bioequivalence reporting from IND-exempt studies. As the occurrence of an SAE is very unusual in these types of studies because the number of subjects is small, they are usually healthy volunteers, and the drug exposure is typically brief, all SAEs regardless of causality need to be reported. Sponsors need to report these events to the FDA Adverse Event Reporting System (FAERS) when there is an existing NDA or ANDA.

In summary, fulfilling the sponsor’s responsibilities to report important drug safety events and potential concerns is multidimensional and involves a number of staff members with different professional expertise. All of these individuals should become familiar with the guidance and FDA’s suggestions for accomplishing this important work.

We will examine the investigator’s and study site’s responsibilities in safety reporting in another installment.

“The guidance provides flexibility regarding review of aggregate safety information for IND safety reporting so that these can be tailored to the investigational agent and clinical trial program.”

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