During a clinical trial of an investigational new drug, it is important to detect whether the drug is causing unexpected health problems in study participants as soon as possible. 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 pre-marketing 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 pre-specified 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 July 21-22, 2015
  • IND Safety Assessment and Communication Expert Meeting, held February 28-29, 2012
  • Adverse Event Reporting Expert Meeting, held October 3-4, 2010
• Workshops for sharing experiences and educating stakeholders with case examples

Over the past six years, CTTI's results on IND safety reporting show that sponsors, regulators, patients, and investigators have different perspectives and challenges, but all prioritize patient safety.

Key findings from CTTI's evidence gathering include:

• Sponsors report aggregate data to regulatory bodies but use individual expedited case reports for safety notifications to investigators.
• Investigators are dissatisfied with the high volume and irrelevant content of individual IND safety reports.
• Processing SAEs is time-consuming and costly.
• None of the SAEs reported in CTTI's retrospective survey led to changes in informed consent, risk profile descriptions, or safety monitoring by investigators.

These findings informed CTTI’s broad recommendations on safety reporting processes..

CTTI also investigated sponsors' claims that FDA's IND safety reporting rule presents implementation challenges, especially in global clinical trials. Industry practices at the time included:

• Most sponsors had multidisciplinary teams led by a safety physician to review individual case reports and determine if they met the final rule criteria.
• A majority of sponsors did not review unmasked or treatment-stratified data from ongoing masked trials when evaluating potential safety signals.
• Most sponsors used external resources and experts for safety evaluations on an ad hoc basis, except for DMCs reviewing unmasked or treatment-stratified data.
• Serious, unexpected, and suspected adverse reactions were reported to the FDA in an expedited manner, determined by an individual reviewer with support from a safety team. Some sponsors relied on conservative judgments for causality.

These findings, along with expert discussions, informed CTTI's specific recommendations on IND safety reporting.

CTTI focused on IND safety reporting in oncology trials due to the severity of the disease and high incidence of adverse events, with results applicable to other trials:

• Analysis showed a slight increase in expedited IND safety reports submitted to the FDA after 2010, with a majority not compliant with the final rule.
• Investigators and study staff received a high volume of expedited reports, many of which were not processed due to non-compliance with institutional review board requirements and FDA rules, increasing workload.
• Reports lacking actionable information did not improve trials or enhance patient safety.
• Despite sponsors' efforts to reduce report submissions, both the FDA and investigators were dissatisfied with the number and quality of expedited reports.

At a 2015 expert meeting, suggestions for improving safety reporting included direct sponsor-FDA interaction, additional FDA guidance or education, examples of successful practice changes, enhanced communication, and training programs. A CTTI webinar shared challenging oncology case studies demonstrating quality and compliant IND safety reporting.

A CTTI survey found that investigators and research staff believe electronic portals could increase the efficiency of expedited safety reporting but are difficult to use and add complexity.

CTTI's IND Safety Advancement Project Team developed recommendations for Desired Attributes of Electronic Portals for Expedited Safety Reporting to address these issues.

• 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

Organization affiliations are listed as active affiliations during the project.

*Indicates former project manager, team leader, or team member.