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.

This is the second installment of a two-part series summarizing two recent FDA draft guidances on safety reporting for investigational products (drugs and biologics) and devices. The first installment covered the sponsor’s responsibilities, as well as FDA’s philosophy on the development of safety monitoring plans. This installment summarizes the draft guidance, entitled “Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices,” that focusses on investigator responsibilities. This guidance is interesting as it is one of the few times that an FDA guidance focuses on the responsibilities of investigators only. It is applicable to clinical studies conducted under Investigational New Drug Applications (INDs) and Investigational Device Exemptions (IDEs) and is designed to help investigators identify safety information that is considered to be an “unanticipated problem regarding risk to human subjects or others” and therefore requires prompt reporting to sponsors and institutional review boards (IRBs). For the sake of brevity, the term ‘drug safety’ is used below to represent safety reporting considerations for all investigational products.

In order for sponsors to fulfill their investigational drug safety reporting requirements, investigators also must understand and comply with their reporting requirements. Because it is the sponsor’s responsibility to submit drug safety reports to FDA and to all investigators studying the investigational product, and to confirm that IRB reporting is complete, sponsors must receive timely drug safety reports from clinical study sites. Drug safety reporting to the site IRB is the investigator’s responsibility unless a central IRB is used and the Sponsor has taken on this responsibility. This guidance helps to clarify for all relevant parties, the responsibilities that fall directly on investigators.

The regulations require that the investigator immediately report to the sponsor any serious adverse event (SAE), regardless of whether the investigator believes the SAE is related to the administration of the product. This includes SAEs that are expected to occur in the study population independent of exposure to the product as well as those listed in the Investigator Brochure. It remains a challenge for sponsors to receive reports of these events in a timely fashion, as they may be overlooked by study site staff because they are expected in the population being studied. In the end, this may result in untimely drug safety reporting to the sponsor leading to a delay in sponsor review and subsequent reporting to FDA.

In studies in which trial endpoints meet the criteria for SAEs (e.g., disease progression in the oncology setting, or myocardial infarction, stroke, or death in trials evaluating drugs intended to treat cardiovascular conditions), the investigator must report these as endpoints, in accordance with the protocol (e.g., where the protocol states these should be reported as endpoints), and not as SAEs unless there is evidence suggesting a causal relationship between a drug and an event (e.g., death from anaphylaxis after exposure). Even if such an event is a component of the endpoint (e.g., all-cause mortality), SAEs meeting this criterion must be immediately reported to the sponsor.

As outlined in the drug safety reporting guidance, ‘immediately’ is as soon as feasible after the investigator recognizes an event is an SAE and obtains relevant information such as a specified subject, a suspected drug (if any), the reporting source (if not the investigator/study staff), and a clinical description of the event, including an assessment of whether a reasonable possibility exists that the drug caused the event. The general time frame for reporting the information is 24 hours.

Investigators are not required to determine whether an event is unexpected; this determination is the sponsor’s responsibility. To determine whether an SAE meets the definition of a suspected adverse reaction (SAR), wherein there is a reasonable likelihood that the product caused the event, the sponsor must evaluate all available information and make the final judgment. Although the sponsor is ultimately responsible for determining causality, the investigator is also required to provide their assessment of causality given they monitor the subject’s response to the drug and are knowledgeable about the subject’s clinical state. As a result, the investigator may be sensitive to distinctions between events that may be related to study therapy exposure versus those caused by the underlying disease process and/or concomitant therapies.

In addition to sponsor reporting requirements, investigators have IRB reporting requirements which include reporting all “unanticipated problems involving risk to human subjects or others.” In the drug safety reporting guidance, FDA makes it clear that a serious and unexpected AE that meets the criteria for an IND drug safety report is also an “unanticipated problem,” and must also be reported to the IRB by the investigator. An additional investigatory responsibility is the review of IND drug safety reports and reports of SAEs from IND-exempt bioavailability/bioequivalance (BA/BE) studies. In FDA’s view, this is essential for protecting the safety of trial subjects. In this guidance, FDA highlights that the review of these reports and submission to IRBs is an important investigator responsibility. In cases where the sponsor has taken on the responsibility of IRB reporting, the investigator does not need to duplicate the reporting but is still responsible for the review component.

There are also events that do not meet the requirements for drug safety reporting but would be considered unanticipated problems involving risk and therefore require reporting to the IRB by the investigator. These may include medication errors, breach of confidentially, or untimely destruction of study records.

While the concept is the same, the safety reporting requirements for devices use slightly different terminology. The IDE regulations require investigator reporting of unexpected adverse device events (UADEs) to sponsors and IRBs. Again, while the investigator is required to provide a causality assessment, the final causality assessment is the sponsor’s responsibility.

It is the sponsor’s responsibility to immediately conduct an evaluation of each UADE received and report the results to FDA, all reviewing IRBs, and all participating investigators within 10 working days after the sponsor first receives notice of the event. What qualifies as a UADE may vary depending on the device and the manner in which it is used. The investigational plan should include risk information to aid investigators in identifying and assessing potential UADEs.

In summary, fulfilling the investigator’s responsibilities to report important drug and device safety events and concerns is multi-faceted. Understanding the investigator’s responsibilities, and how they support the sponsor’s responsibilities, is key to timely drug safety reporting.

“This guidance is interesting as it is one of the few times that an FDA guidance focuses on the responsibilities of investigators only.”

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