ASCO has released recommendations to streamline serious adverse events reporting for cancer clinical trials. The ASCO research statement, published December 13 in the Journal of Clinical Oncology, discusses strategies to address the high volume of uninformative adverse events reports submitted to the U.S. Food and Drug Administration (FDA) and investigators.
To protect patient safety, current regulations require research sponsors to report certain serious adverse events experienced by patients in a clinical trial to the FDA and investigators through an expedited process. The authors note that, in order to qualify for expedited reporting, adverse events must be “suspected adverse reactions that are both serious and unexpected,” according to FDA guidelines. This definition incorporates three elements – all of which must be met for the event to meet the FDA’s standards for expedited reporting:
- “Serious” – the event must be serious or life threatening, such as death, hospitalization, incapacitation, among others;
- “Unexpected” – the event is not listed in the study protocol or investigator brochure; and
- “Suspected” – there is a reasonable possibility the study drug caused the event.
Since the early 2000s, the FDA and investigators have experienced an influx of adverse event reports that do not adhere to expedited adverse events reporting requirements. In 2010, the FDA released a Final Rule to provide further clarity and guidance on expedited adverse events reporting, however, over reporting has remained a persistent issue, according to ASCO.
The authors assert that the high volume of uninformative reports hinders patient safety and imposes a substantial toll on FDA and research site time and resources. As the statement notes, a random audit of expedited adverse events reports submitted to the FDA in 2016 found that only 14 percent of 160 adverse events reported to the FDA we helpful in assessing patient safety. Cancer researchers and sites experience a similar strain due to the high volume of adverse events reporting. A Clinical Trials Transformation Initiative (CTTI) survey discussed in the statement found cancer researchers see this as a substantial and increasing burden with 60 percent of site investigators and staff respondents indicating that they spend more than 10 hours each month processing safety reports.
As the ASCO research statement explains, clinical trial sponsors and contract research organizations (CRO) face a number of challenges in reducing the amount of uninformative reports they submit to the FDA. Sponsor respondents to a CTTI survey pointed to issues such as international differences in reporting requirements, concerns with liability, and infrastructure limitations and financial barriers to internally updating reporting systems and processes.
Acknowledging the persistence of this issue and its negative impact on stakeholders across the research community, ASCO held a workshop in March 2017 on streamlining adverse events reporting for cancer clinical trials. Attended by researchers, industry representatives, patient advocates, and officials from FDA and National Cancer Institute, the workshop discussed ways to decrease over-reporting, as well as best practices for adverse events reporting for sponsors, CROs, and research sites.
The workshop included presentations by sponsors that have been able to adopt better processes and practices to reduce the volume of uninformative adverse events reports they submit. Success story examples, as well as recommendations for implementing best practices for adverse events reporting and improving reporting processes across the cancer research community are outlined in ASCO’s statement.
ASCO Research Statement Recommendations
Sponsors and CROs Should Adopt Best Practices for Reporting Adverse Events
Sponsors should fully implement the FDA’s 2010 Final Rule. To this end, the statement notes several common practices of sponsors who have successfully improved their adverse events reports to only reporting on actionable adverse events:
- Shift company culture to fully commit to reducing uninformative reporting.
- Establish a consistent standard for determining whether an event could have reasonably been caused by the investigational drug.
- Implement a system to monitor appropriate staff and company-wide adverse event reporting.
- Ensure medical review staff are appropriately trained to report adverse events effectively.
Moreover, sponsors and CROs should be receptive to feedback from the FDA, which regularly communicates with sponsors on the need to reduce uninformative reports, as well as investigators, and other stakeholders who may also share feedback regarding their adverse event reporting practices.
Finally, sponsors and CROs should increase transparency regarding their adverse event reporting practices to incentivize streamlined reporting and allow research sites to consider these practices when deciding whether to open a clinical trial.
Researchers and Research Sites Should Adopt Best Practices for Reporting Adverse Events to Sponsors
Improved training processes could help to increase understanding of the FDA’s expedited reporting requirements. Site training programs should stress the importance of accurately and completely reporting serious adverse events. Additionally, sponsors often have their own organization-specific training programs for investigators. Sponsors should utilize centralized training for investigators to improve efficiencies and reduce the burden of multiple training requirements on investigators.
Standard operating procedures can be used to prevent uninformative adverse events reporting and improve detection and evaluation of adverse events during a clinical trial. Research sites should utilize standard operating procedures for expedited reporting of adverse events based on the FDA’s 2010 Final Rule.
International Regulatory Agencies Should Harmonize the Regulations for Adverse Events Reporting
A primary issue expressed by sponsors in attempting to reduce the volume of uninformative reports is the lack of consistency between international safety reporting requirements – specifically differences in FDA requirements and the International Conference on Harmonization (ICH) E2A Guidelines, which are followed by other countries. Some sponsors have successfully implemented processes to submit expedited adverse events reports separately based on FDA and ICH criteria, however, such a system can be costly to develop and execute. To overcome this challenge, stakeholders worldwide should support international regulatory harmonization.
All Stakeholders Should Use Modern, Digital Technology to Report Adverse Events
Safety data is often reported through an electronic portal however, investigators often express that they encounter difficulties when using these systems. A centralized, globally available portal to access safety data and report adverse events should be developed by a neutral party to overcome existing technological barriers and limitations of sponsor-specific reporting systems. Coordination with FDA and international agencies on electronic collection of safety data will be crucial in the development of a centralized portal.
Read the full statement in the Journal of Clinical Oncology.