Safety Reporting From Clinical Trials—What Regulators Expect

Monitoring patient safety is an integral and critical part of the clinical trial process. The objective of collecting safety data from clinical trials is early detection of important safety signals, protecting patients from unnecessary risks, and developing the safety profile of the drug contributing to its benefit-risk assessment. Safety data from ongoing clinical trials has a direct impact on the safety and clinical care of patients enrolled in these trials. The ultimate goal of clinical trial safety monitoring is to evolve medically relevant safety label information for the product under development. Mandates by regulatory authorities around the documentation and reporting of serious events have evolved significantly to help ensure the safety of clinical trial subjects.

The regulatory landscape for safety monitoring of healthcare products has changed considerably in recent years. The FDA published a final rule amending the safety reporting requirements under 21 CFR part 312 (IND studies) and 21 CFR part 320 (BA-BE studies) in September 2010. The US regulations (effective March 2011) and the European Commission's detailed guidance (CT 3, June 2011) on the collection, verification, and presentation of adverse event/reaction reports arising from clinical trials lay strong emphasis on early reporting of serious events with a reasonable possibility of being associated with the drug, so that safety analysis is not confounded by unnecessary noise and product safety can be assessed more meaningfully.

Under the previous regulations, the IND sponsors were often reporting to the agency and clinical investigators, in an expedited manner, a substantial number of serious adverse events, which may or may not have had any relationship to the study drug. This caused the safety system to be clogged with a lot of distracting information, probably leading to masking of true safety signals. Under the current regulations the IND sponsors must report to the agency and the investigators, on expedited basis, only those events that are serious, unexpected (not listed in the investigator's brochure), and are suspected to be caused by the drug (i.e., there is a reasonable possibility or evidence to suggest that the drug caused it).

Precautions to ensure patient safety require that clinical investigators must report to the sponsors all serious adverse events on an expedited basis, regardless of whether they are considered drug-related or not, relieving them of the burden of making a judgment on the causal association with the drug. Current regulations recognize that the sponsor has the broadest view of the drug's history and characteristics, and is therefore in the best position to attribute causality. Events which cannot be analyzed as single cases need to be assessed on an aggregate basis and reported if there is a difference in the reporting rates between the drug and the control groups. The regulations also make a distinction between the adverse events and mortality and morbidity endpoints, which need to be analyzed as per the study protocol. As an additional measure to protect patient safety, the FDA also recommends that proceedings of the data safety monitoring boards be sent to the institutional review board (IRB) for review.

Under the current European regulations (CT3, 2011/C, 172/01, June 2011) the investigator must report all serious adverse events immediately to the sponsor except for those that the protocol or investigator's brochure identifies as not requiring immediate reporting. The sponsor needs to report on expedited basis only the SUSARs (serious, unexpected, suspected, adverse reactions), preferably unblinded, within seven days for fatal or life threatening events and 15 days for the other SUSARs. The sponsor reports the SUSAR directly as an individual case safety report (ICSR) to the national competent authority (CA) of the relevant member state and also indirectly through the electronic gateway to the EudraVigilance Clinical Trial Module (EVCTM). The latter requires registration with the eudravigilance and those sponsors who may not have the resources and experience for electronic reporting may delegate indirect reporting to a partner.

Annual safety reports must be generated throughout the clinical trial and sent to the national CA and the ethics committees/IRBs. These reports must contain a listing of all suspected serious adverse reactions which have occurred over this period and a report of the subjects' safety. Investigators should receive a line listing with a summary of evolving safety issues. There are separate guidelines on periodic safety update reports during the developmental phase in the form of developmental safety update reports in the European Union and IND annual safety reports in the United States. Though the regulations focus on serious adverse events, the sponsor is expected to monitor all adverse events during drug development, including non-serious ones.

In conclusion, regulations ensure that assessment of safety during clinical development is more meaningful and sponsors need to have a more systematic approach to safety assessment of their investigational products. Managing clinical trial safety data is a collaborative process. Investigators, sponsors/CROs, ethics committees, data safety monitoring boards, and regulators all share the responsibility for protecting clinical trial subjects by scrutinizing and evaluating safety data proactively and on an ongoing basis.

—Suhasini Sharma, Director, Medical Affairs; Darshan Bhatt, Consultant, Drug Safety; Chitra Lele, Chief Scientific Officer all at Sciformix Corporation, www.sciformix.com, ask@sciformix.com.