New FDA Clinical Study Safety Monitoring Requirements

Michael Silverman comments on the new FDA Clinical Study Safety Monitoring Requirements including the ability to evaluate events in context and the new definition of unexpected events

I’ve come a little late to the topic, but I’m now studying up on the newly revised FDA requirements for safety – and specifically, serious adverse event (SAE) – reporting for IND trials. If you are just learning about this, please understand that 21CFR320.32, the section of statute relating to IND safety reporting, was subject to an update in September 2010. Accordingly, the changes come into effect at the end of March 2011. I have had a number of conversations over the past few weeks with colleagues, pharmcovigilance experts, and clinical contract research organizations both here and abroad about what steps they are taking to prepare for the changes.

I have also familiarized myself with the September 2010 FDA Draft Guidance document, “Safety Reporting Requirements for INDs and BA/BE Studies”. The new Guidance is a very thoughtful and interesting document, and well worth reading for anyone involved in this aspect of new drug development. For more information click on this link. Of particular note are new definitions for “adverse event” and “suspected adverse reaction”; revised definitions for “serious”, “life-threatening”, and “unexpected”; and new investigator reporting requirements (appearing in 21CFR312.64(b)).

As an industry physician who acts as Medical Monitor for a number of clinical trials in a variety of therapeutic areas, there are 2 aspects of the new regulation that I find especially notable for their impact on both my philosophy and my activities with respect to SAE evaluation and reporting. The first is that FDA, in an effort to make safety reports “more informative”, has given the Sponsor (and, by extension, the Medical Monitor who is conducting safety evaluations on behalf of the Sponsor) more latitude in exercising judgment about whether there is a “reasonable possibility” that an event is caused by the investigational drug. This change is based on the theory – certainly valid, in my experience – that the Sponsor has the broadest view of the drug’s history and characteristics, and is therefore in the best position to place an SAE in proper context. Whereas in the past, safety monitors have generally felt constrained by an investigator’s attribution of causality, and reluctant (or forbidden) to overrule it, the new regulations now empower us to evaluate every event in context and, where appropriate, judge that an event is more likely to be attributable to underlying disease, intercurrent illness, or concomitant medication than to investigational drug.

The second intriguing change relates to how much the information in a Clinical Investigator Brochure (CIB) mitigates the ruling of “unexpectedness”. For a drug that has never been tested in man, it is always a challenge to draft the risk-benefit and investigator guidance sections of a CIB in the absence of clinical data. My general approach, in addition to of course noting animal toxicology data, has been to add human safety information about drugs in the same class – as another tool for informing physicians and patients on what might be expected effects of the new drug. The new rule now explicitly states that the definition of “unexpected” includes effects which are mentioned in the CIB as occurring with the particular drug class or as anticipated from the pharmacological activity, but not having been reported with the drug under investigation.

Overall, I feel the new policies will have a positive effect on the evaluation and interpretation of SAEs in IND clinical trials. If you have a perspective – especially from experience with the European system of SAE reporting, with which FDA is now more closely harmonized – I would enjoy hearing from you.

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries. The goal of this blog is to provide a forum to discuss the challenges and intricacies of clinical development, as well as the testing of pharmaceutical, biotechnology and medical device products in man.

Over the next several months, I hope to address a number of issues that are of interest to you (and me). If you have any particular questions you would like me to address, send me an email at

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Copyright © 2011 BioStrategics Consulting Ltd.



About BioStrategics Consulting Ltd

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical and biotechnology industries
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