Safety Analytics Webinar Series: Interdisciplinary Safety Evaluation for Learning and Decision-Making

In 2010, the FDA issued final regulations addressing safety reporting requirements for INDs. The final rule states that a clinical trial sponsor must report serious unexpected suspected adverse reactions for which there is evidence to suggest a causal relationship between the drug and the adverse event. In addition, the final rule states that increases in the occurrence rates of serious adverse reactions over those listed in the protocol or investigator brochure must be reported as expedited IND safety reports. For events which are known consequences of the underlying condition under investigation, or events that commonly occur in the study population independent of drug exposure, an aggregate analysis should be performed to identify events occurring more frequently in the drug treatment group compared to a concurrent or historical control group.

The important thing is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity
– Jacqueline Corrigan-Curay (Principal Deputy Center Director in the FDA’s Center for Drug Evaluation and Research)

Sponsors and the FDA have been working together to improve approaches for assessing accumulating safety data, with progressively more cross-functional teams for planning and coordinating programme-level safety assessments and more guidance on aggregate safety assessments. To meet the spirit of the IND safety reporting final rule, sponsors have developed processes and procedures to evaluate, assess and act on accumulating safety information during development on an ongoing basis. Some multidisciplinary teams have been implementing procedures for review of aggregate blinded clinical trial data, minimising the need to intentionally unblind data in ongoing studies. 

An Aggregate Safety Assessment Planning (ASAP) process (Hendrickson et al., 2021) is needed to scientifically evaluate the accumulating programme-level safety information – leveraging existing processes such as medical safety review of individual cases and medical monitoring of individual studies. A proactive and systematic process supports ongoing characterisation of the product safety profile to prepare for regulatory filing activities and for responses to regulatory queries, consistently and authoritatively communicating the safety story throughout clinical development.

Plans are nothing; planning is everything
– Dwight D. Eisenhower

The ASAP process strengthens cross-functional communication and empowers the Safety Management Team (SMT) to plan and coordinate all of the Ongoing Aggregate Safety Evaluations (OASEs) needed to understand, characterise and communicate the safety story: 1) Overall Safety Assessment (for learning) and 2) Assessment of Safety Topics of Interest (for decision-making). Safety topics of interest facilitate the use of consistent safety endpoint definitions across studies in the programme and ensure alignment between aggregate safety assessment and study level monitoring and evaluation of safety data. The safety strategy guides the OASEs and could enable the leveraging of technology in regulatory decision making, such as including interactive safety graphics in a submission.

Blinded-OASE

• To evaluate the general safety profile of the product (without unblinding)

• To detect emerging safety topics while studies are ongoing

• To evaluate risk elevation for select safety topics of interest

Unblinded-OASE

• To support ongoing characterisation of the product safety profile

• To leverage the results for planning and preparation of aggregate safety-related documents in support of a regulatory filing

• To support responses to health authority requests related to specific safety inquiries

The safety profile of the product emerges and is documented in the Development Core Safety Information and Investigators Brochure and is communicated out in documents such as the Development Safety Update Report, the Integrated Summary of Safety and the Common Technical Document. The iterative process of learning and decision-making continues and is documented in the Company Core Safety Information and Product Label and is communicated out in documents such as the Risk Management Plan and the Periodic Benefit Risk Evaluation Report, as well as in responses to regulatory queries. Proactive safety assessments enable effective risk management: characterising and managing risks to deliver effective medicines to the right patients, and allowing well-defined patient populations to realise important health benefits of effective drugs.

Previous Webinars: 

Click the links below to view the summary, slides and recording.