Reporting of coagulation disturbance SUSAR’s from studies with direct factor Xa inhibitors

Dr. Siegert, Joachim1,2, Heinrich-Gräfe, Uta2, Dr. Schindler, Christoph2, Brecht, Beate2, Prof. Dr. Kirch, Wilhelm1,2. 1Ethics committee of the Medical Faculty of TU Dresden, Dresden Germany, Fiedlerstrasse 27, 01307 Dresden, Germany ; 2Institute of Clinical Pharmacology, Medical Faculty, Technical University Dresden, Dresden, Germany, Fiedlerstrasse 27, 01307 Dresden, Germany.

In clinical trials investigators have to inform the sponsor of the corresponding trial immediately concerning all serious adverse events (SAE). Thereafter the sponsor has to inform the competent authorities and concerned ethics committees (EC) within 7 or 15 days about all suspected unsuspected serious adverse reactions (SUSAR). Thereby the sponsor needs to monitor and evaluate the incoming SAE to extract the SUSAR to send onward to authorities and EC.

Within this task the drug safety department of the sponsor has to distinguish between events (something that happened during the trial without a causal relationship, e.g. side effects or events due to the basic illness) and reactions (at least a causal relationship between the event and the suspected drug is highly likely). Furthermore it has to be distinguished between known (reactions listed in investigators brochures or previous SUSAR reports) and unexpected reactions.

During a short time period (approx. 1 month) for two direct factor Xa inhibitors 7 bleeding complications (haemoptysis, gastrointestinal haemorrhage, bloody urine and brain haemorrhage), 6 cases of lung embolism, 1 stroke and 3 cases of deep vein thrombosis were reported as independent unexpected reactions.

Patients treated with factor Xa inhibitors are usually at risk of thromboembolic complications due to their basic illness and bleeding complications are a well known risk with the use of the substances.

Thereby the evaluations of drug safety departments of sponsors, that such events are unexpected reactions caused by the drug use seem not to be conclusive. Furthermore they are in good agreement with earlier independent observations1 that at least 85 % of the SUSAR reports sent to ethics committees do not fulfill the legal definitions given for expedited SUSAR reporting.

S. Trillenberg, et al. Analysis of SUSAR reports sent to an Ethics Committee, P 9, 10. VKliPha Congress, Berlin, 2008.