Project:

Safety Reporting

overview icon Overview

Advancing IND Safety Reporting

Timely and accurate safety reporting is critically important in clinical research. CTTI offers tools to improve the quality and efficiency of safety reporting for clinical trials conducted under an investigational new drug application (IND). Sponsors can use CTTI’s recommendations for IND Safety reporting to reduce irrelevant reports and increase their adherence to U.S. Food and Drug Administration (FDA) requirements. The recommendations were developed in response to challenges that followed the FDA’s Final Rule for reporting serious and unexpected adverse drug reactions.

The recommendations outline approaches for better assessment and communication of IND safety issues, implementing safety assessments, and adopting aggregate reporting to enhance efficiency and interpretability. Additionally, in response to persistent challenges related to reporting volume and quality, CTTI gathered evidence and convened a multi-stakeholder expert meeting to investigate barriers and solutions to full compliance with the safety reporting rule. Results on safety reporting experiences in the oncology setting highlight areas for improvement that are also relevant to other therapeutic areas. At the expert meeting, 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 offers education on the final rule and explores practical case studies to help sponsors and investigators work through challenging reporting scenarios. CTTI also examined strategies for using electronic portals to improve safety reporting. The resulting e-portal recommendations can be applied to reduce complexity of portal technologies and create more usable systems for investigators and research staff.

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Discover Additional Deliverables Generated From This Project

Webinar

Case Studies on Expedited IND Safety Reporting

Poster

IND Safety Reporting: Final Results and Best Practices from the Clinical Trials Transformation Initiative IND Safety Advancement Project, presented at ASCO 2016

Expert Meeting Materials

Summary, presentations, and more from CTTI's Expert Meeting on IND Safety Advancement held July 21 - 22, 2015

Publication

Industry Practices for Expedited Reporting to Investigators Conducting Research Under an IND (Published in Therapeutic Innovation & Regulatory Science)

Publication

Optimizing Expedited Safety Reporting for Drugs and Biologics Subject to an Investigational New Drug Application (Published in Therapeutic Innovation & Regulatory Science)

Press Release

Clinical Trials: Do Participants Feel Safe?

Publication

Participants’ Perspectives on Safety Monitoring in Clinical Trials published in Clinical Trials

Expert Meeting Materials

Executive summary, presentations, and more from CTTI's Expert Meeting onn IND Safety Assessment and Communication held February 28 - 29, 2012

Press Release

New Recommendations from Public-Private Partnership Aim to Improve Clinical Trial Quality and Safety

Expert Meeting Materials

Summary, presentations, and more from CTTI's Expert Meeting on Adverse Event Reporting held October 3 - 4, 2010

CTTI was cited in the FDA’s newest draft guidance on IND safety reporting.

“Most IND safety reports are distributed via e-portals, and this will likely only increase in coming years. The CTTI recommendations, if fully implemented, will improve the accessibility, interpretability, and accountability of e-portal safety data reporting. This has great potential to enhance the safety of participants in clinical trials.” 

Ray Perez, MD, Medical Director, University of Kansas Clinical Research Center, University of Kansas Medical Center

Page 1 Project Progress

Identify Research Impediments
100%
Gather Evidence
100%
Analyze & Interpret Findings
100%
Develop Recommendations
100%
Disseminate & Implement
100%

in detail icon In Detail

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.

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.

Project Team Members

Role Name Affiliationsort descending Project
Team Leader Howard Greenberg ACCP SAE Reporting
Team Member Kevin Jones Accurate Clinical Trials SAE Reporting
Team Leader Jose Vega Amgen IND Safety
Team Leader Greg Nadzan Amgen SAE Reporting
Team Leader Sundeep Sethi Amgen SAE Reporting
Team Leader Jose Vega Amgen SAE Reporting
Team Member David Balderson Amgen IND Safety
Team Member Patricia Hurley ASCO IND Safety Advancement
Team Member Elliott Levy Bristol Myers Squibb IND Safety
Team Member Janice Wherry Bristol Myers Squibb IND Safety
Team Member Rachpal Malhotra Bristol-Myers Squibb SAE Reporting
Team Member Lauri Carlile Chesapeake IRB IND Safety Advancement
Project Manager Annemarie Forrest Clinical Trials Transformation Initiative IND Safety Advancement
Team Leader Judith Kramer Clinical Trials Transformative Initiative IND Safety
Team Member Kathryn Flynn Duke University SAE Reporting
Team Leader Robert Califf Duke University SAE Reporting
Team Member Judith Kramer Duke University SAE Reporting
Team Leader Lynda Szczech Duke University SAE Reporting
Team Leader Kevin Weinfurt Duke University SAE Reporting
Team Member David Vock Duke University SAE Reporting
Team Member Caroline Rosewell Eli Lilly IND Safety Advancement
Team Member Shanell Whitney Eli Lilly IND Safety Advancement
Team Leader Marsha Millikan Eli Lilly IND Safety Advancement
Team Member Janet Roepke Eli Lilly IND Safety Advancement
Team Leader Patrick Archdeacon Food and Drug Administration IND Safety
Team Leader Patrick Archdeacon Food and Drug Administration IND Safety Advancement
Team Leader Jonathon Jarow Food and Drug Administration IND Safety Advancement
Team Member Ann Meeker-O'Connell Food and Drug Administration SAE Reporting
Team Member Janet Norden Food and Drug Administration SAE Reporting
Team Leader Kathleen Uhl Food and Drug Administration SAE Reporting
Team Member Leonard Sacks Food and Drug Administration SAE Reporting
Team Member Cheryl Grandinetti Food and Drug Administration IND Safety
Team Member Philippe Bishop Genentech - a member of the Roche Group SAE Reporting
Team Member Miklos Salgo Genentech-a member of the Roche Group SAE Reporting
Team Member Suzanne Gagon ICON SAE Reporting
Team Leader Nancy Roach Individual Patient/Caregiver IND Safety Advancement
Team Member Jane Perlmutter Individual Patient/Caregiver IND Safety Advancement
Team Member Jose Vega Merck & Co, Inc IND Safety Advancement
Team Member Krupa Patel Merck & Co, Inc IND Safety Advancement
Team Member Nina Stuccio Merck & Co, Inc. IND Safety Advancement
Team Member Shanda Finnigan National Institutes of Health IND Safety Advancement
Team Leader Maria Luisa Bonura Pfizer Inc IND Safety Advancement
Team Member Margaret McLaughlin Pfizer Inc SAE Reporting
Team Member Maria Bonura Pfizer Inc IND Safety Advancement
Team Member Heather Macy Pfizer Inc. SAE Reporting
Team Member Diane Ryan Pfizer Inc. SAE Reporting
Team Member Jennifer Sorgen Pfizer Inc. SAE Reporting
Team Member Greg Hockel PharmaNet SAE Reporting
Team Member Leann Fieldstad Roche SAE Reporting
Team Member Dorothy DiChristofano Sanofi-Aventis SAE Reporting
Team Member Renee Smith Sarah Cannon Research Institute IND Safety Advancement
Team Member Tracy Swan Treatment Action Group SAE Reporting
Team Leader Raymond Perez University of Kansas IND Safety Advancement
Team Leader Susan Ellenberg University of Pennsylvania SAE Reporting
Team Member Jeremy Day US Oncology IND Safety Advancement