Reporting of cardiovascular SUSAR’s from clinical trials in patients with multiple myeloma

Heinrich-Gräfe, Uta1, Dr. Siegert, Joachim1,2, Dr. Schindler, Christoph1, Schroeder, Jane 1, Boehme, Arnim1, Prof. Dr. Kirch, Wilhelm1,2. 1Institute of Clinical Pharmacology, Medical Faculty, Technical University Dresden, Dresden, Germany, Fiedlerstrasse 27, 01307 Dresden, Germany ; 2Ethics committee of the Medical Faculty of TU Dresden, Dresden Germany, Fiedlerstrasse 27, 01307 Dresden, Germany.

Cardiovascular multiple myeloma complications are hyperviscosity of blood (embolism and stroke), thrombopenia (bleeding complications) amyloidosis (cardiomegaly, ayrrhytmias).

In clinical trials investigators and drug safety departments have to distinguish between complications of the basic disease (events) and adverse drug reactions due to the therapy of the disease. Furthermore it has to distinguished between expected (e.g. listed in investigators brochures or previous SUSAR reports) and unexpected reactions (which might be reported as SUSAR).

According to the legal requirements physicians treating patients within clinical trials have inform the sponsor of the corresponding trial immediately concerning all serious adverse events (SAE) that occur during the trial. 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 be reported to authorities and EC1.

During a short time period (approx. 1 month) for two clinical trials (immunomodulator and proteasome inhibitor) treating multiple myeloma 8 cardiovascular SUSAR were reported as unexpected reactions. These cases included sudden cardiac death, cardiac arrest, 3 cases of tachycardia/arrhythmia, cardiac infarction, collapse and dyspnoe due to pulmonary embolism, prolonged QTc and cardiomyopathia.

Due to the fact that all these reactions might be explained as complications of multiple myeloma (events) and thereby have not to classified as unexpected the appropriateness of the expedited SUSAR reporting for these medical conditions should be questioned. According to earlier independent observations² at least 85 % of the SUSAR reports sent to ethics committees do not fulfill the legal definitions given for expedited SUSAR reporting.

J. Siegert, et al. Reporting of coagulation disturbance SUSAR’s from studies with direct factor 10a inhibitors, New Drugs in Cardiovascular Research, Dresden 2009.
S. Trillenberg, et al. Analysis of SUSAR reports sent to an Ethics Committee, P 9, 10. VKliPha Congress, Berlin, 2008.