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CTTI was cited in the FDA’s newest draft guidance on IND safety reporting.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