During a clinical trial of an investigational new drug, it’s important to detect whether the drug is causing unexpected health problems in study participants as soon as possible. In multi-center clinical trials, each site investigator is required by law to notify the study sponsor if one of the study participants at their site has a serious adverse event (SAE). If the reported SAE is unexpected (i.e., not already detailed in the product’s investigator’s brochure) and suspected (i.e., has a possible causal association with the investigational drug), the sponsor is required to send an expedited notification to the FDA and all other investigators studying the same investigational product.

To uphold their obligations to study participants and to institutional review boards, investigators need the reports they receive from sponsors to be informative about the developing profile of risks for the investigational drug. Many investigators had raised concerns about the number and interpretability of expedited safety reports they were receiving from study sponsors. Without adherence to proper safety reporting guidelines, the chance of missing a true safety signal within the high volume of irrelevant reports increases greatly, which poses a threat to patient/public health. CTTI sought to provide empirical evidence about the system that was in effect for expedited reporting of SAEs to investigators conducting research under an IND and to consider potential modifications that would more efficiently communicate useful information to investigators, enabling the optimal care of study participants.

During the course of CTTI’s work, the FDA issued a Final Rule on premarketing safety reporting requirements. CTTI’s recommendations are aligned with the Final Rule requirements and support its goal of reducing the volume of uninterpretable and irrelevant safety reports submitted to regulators and investigators. However, sponsors perceived several challenges in implementing the final rule, in particular with regard to global clinical trials. CTTI initiated another project to understand sponsors’ practices and develop recommendations for successful approaches for safety reporting and adherence to the final rule. The CTTI recommendations for IND Safety reporting detail specific strategies sponsors can employ to reduce irrelevant reports and increase their adherence to FDA requirements. These recommendations support and supplement FDA guidance released to clarify that sponsors should not submit expedited safety reports for individual cases of serious and unexpected adverse events for which there is little reason to believe that the drug caused the event.

Despite both guidance from regulators and CTTI’s recommendations, anecdotal reports indicated that problems remain, particularly in oncology clinical trials. CTTI collected data from sponsors and investigators on remaining challenges to compliance with FDA requirements. The results from the oncology setting are generalizable to other therapeutic areas and provide insight into ways to further improve safety reporting. CTTI also convened an expert meeting, which identified methods to spur improvement in safety reporting: direct sponsor-FDA interaction, additional guidance or education from the FDA, examples and case studies of successful practice changes, enhanced communication between parties, and training programs. A CTTI webinar offers education on the final rule and explores practical case studies to help sponsors and investigators work through challenging reporting scenarios. Additionally, with input from multiple stakeholders, CTTI developed recommendations for Desired Attributes of Electronic Portals for Expedited Safety Reporting. These recommendations address the complexity of electronic portals, which can hamper investigators and research staff from using the systems effectively to increase the quality and efficiency of expedited safety reporting to research sites.

• IND Safety Advancement: Investigational New Drug Safety Reporting: Advancing CTTI Recommendations (2014 - 2016)
• IND Safety: Investigational New Drug Safety Assessment and Communication (2011-2013)
• SAE Reporting: Improving the System of Reporting and Interpreting Unexpected Serious Adverse Events to Investigators Conducting Research Under an Investigational New Drug Application (2009-2011)

• Understand what the sponsor challenges are to full implementation of the IND safety reporting rule in oncology trials
• Understand sponsor motivation to change practice of IND safety reporting in oncology trials in order to fully comply with the IND safety reporting rule
• Understand challenges to investigator receipt and management of IND safety reports at oncologic investigative sites and coordinating centers
• Facilitate adoption of best practices for communicating and managing IND safety reports consistent with FDA guidance, the IND safety rule and CTTI recommendations

Serious unexpected safety adverse reports will be communicated to investigators and regulators efficiently, containing information that is valuable to all stakeholders and in full compliance with current regulations.

• Use of CTTI’s Recommendations, Improving Reporting of Unexpected Serious Adverse Events (SAEs) to Investigational New Drug (IND) Investigators, can improve sponsors’ approaches to submitting expedited SAE reports to investigators, lessening the burden on investigators.
• With assistance from the CTTI Recommendations, IND Safety Assessment and Communication, sponsors are better positioned to address upfront safety planning, implementation of safety assessments, defining thresholds for expedited safety reporting, and managing adverse events that are not prespecified in the protocol.
• CTTI’s results on remaining challenges to safety reporting include suggestions for improvement from the perspective of sponsors and investigators. A CTTI webinar provides education on the final rule and explores practical case studies to help sponsors and investigators work through challenging reporting scenarios.
• Through use of CTTI’s Recommendations for Desired Attributes of Electronic Portals for Expedited Safety Reporting, sponsors can establish consistent functionality across e-portals to improve efficiency and reduce burden on researchers and site staff

• Surveys and interviews (sponsors, investigators) to assess approaches, practices, and challenges
• Evaluation of sample expedited SAE reports
• Focus groups
• Expert meetings
  • IND Safety Advancement Project Expert Meeting, held on July 21 - 22, 2015
  • IND Safety Assessment and Communication Expert Meeting, held on February 28 - 29, 2012
  • Adverse Event Reporting Expert Meeting, held on October 3 - 4, 2010
• Workshops for sharing experiences and educating stakeholders with case examples
• Analysis of 483 forms

The synthesis of CTTI results garnered over the last 6 years on IND safety reporting indicate that although sponsors, regulators, patients, and investigators all have different perspectives on, challenges with, and understanding of safety reporting (and associated regulatory requirements), all parties hold patient safety as a paramount concern.

Results from CTTI evidence gathering indicated the following:

• Sponsors often report aggregate data to regulatory bodies, but they typically communicate safety notifications to investigators using individual expedited case reports.
• Investigators express dissatisfaction with the volume (too many) and content (not relevant) of individual IND safety reports.
• Processing of SAEs is time-consuming and expensive.
• Of the SAEs reported during CTTI’s retrospective survey, none led to a change to the informed consent, the description of the risk profile to patients, or safety monitoring by investigators.

These results informed CTTI’s recommendations that broadly address processes in safety reporting.

Subsequently, CTTI investigated the basis of sponsors’ claims that changes introduced in FDA’s IND safety reporting rule present challenges in implementation, particularly related to global clinical trials. Results from the survey of industry practices found the following practices in place at the time:

• Most sponsors had some type of multidisciplinary team (e.g., “safety team”) generally led by a safety physician, to conduct primary reviews of individual case reports within a given trial and determined whether the reports met the final rule criteria.
• A majority of sponsors surveyed do not review unmasked or treatment-stratified data from ongoing masked clinical trials when evaluating potential safety signals.
• Most respondents use external resources and experts to assist in the safety evaluation of their clinical trial data on an ad hoc basis only. An exception is the use of DMCs to review unmasked data or data stratified by treatment arm from ongoing clinical trials.
• Respondents indicated that individual adverse events deemed to be 1. serious, 2. unexpected, and 3. suspected adverse reactions are reported to the FDA in an expedited fashion, and the determination regarding whether an event meets all 3 definitions is made by an individual reviewer with the support of a larger safety team. Some sponsors still rely on the most conservative judgment to determine causality.

These results, along with discussion at a multi-stakeholder expert meeting informed CTTI’s IND safety recommendations, which provide specific details on considerations critical to decision-making in safety reporting.

A further CTTI project focused specifically on IND safety reporting in oncology trials because safety reporting in these trials still pose considerable challenges due to severity of the disease and the high incidence of adverse events; however, results can be applied to other trials.

• Analysis of expedited IND safety reports submitted to the FDA indicated that the mean number per IND submitted after 2010 slightly increased compared to before 2010, and a majority were not compliant with the final rule. 
• Investigators and study staff still receive a high volume of expedited IND safety reports, but many of these reports are not even processed because they do not meet institutional review board requirements, are not compliant with the FDA rule, and contribute to an increased workload to process. 
• Investigators and site staff indicated that reports lacking actionable information were not used to improve trials or enhance patient safety in any way. 
• While sponsors believe that they have made changes that considerably reduce the amount of reports being submitted, both the FDA and investigators were dissatisfied with the number and quality of expedited IND safety reports.

An expert meeting held in 2015, experts agreed that a cultural change is needed with regard to safety reporting. Suggestions to improve the system and change the culture of safety reporting included the following: direct sponsor-FDA interaction, additional guidance or education from the FDA, examples and case studies of successful practice changes, enhanced communication between parties, and training programs. A CTTI webinar shared challenging case studies in oncology demonstrating the principles of quality and compliant IND safety reporting.

A CTTI survey identified that investigators and research staff believe electronic portals have the potential to increase the efficiency of expedited safety reporting to research sites, but in practice are difficult to use and add to the complexity of the system.

CTTI’s IND Safety Advancement Project Team developed recommendations for Desired Attributes of Electronic Portals for Expedited Safety Reporting to help mitigate these issues for those involved in safety reporting.

Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans, September 2010

Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (Final), December 2012