Deaths in clinical trials

Determining the cause of deaths in clinical trials is extremely important, but this goal is often difficult or impossible to achieve. Investigators should be prepared to present reasons to family members to convince them of the importance of conducting an autopsy. Such an autopsy should include examination of the brain, whenever possible. 

In spite of their lower transfection efficiencies, the advantage of these systems over viral vectors with respect to safety has been highlighted following the recent deaths in clinical trials of viral vector-based gene products in the US. 

Earley A, Lau J, Uhlig K (2013) Haphazard repotting of deaths in clinical trials a review of cases of ClinicalTrials.gov records and matched publications-a cross-sectional study. BMJ Open... 

The benefit of carotid endarterectomy for prevention of recurrent stroke has been studied previously in major trials.25,26 A recent meta-analysis has been completed that has combined these clinical trials to evaluate 6,092 patients.27 Carotid endarterectomy has been shown to be beneficial for preventing ipsilateral stroke in patients with symptomatic carotid artery stenosis of 70% or greater and is recommended in these patients. In patients with symptomatic stenosis of 50% to 69%, a moderate reduction in risk is seen in clinical trials. In all patients with stenosis of 50% to 69% and a recent stroke, carotid endarterectomy is appropriate. In other patients, surgical risk factors and surgeon skill should be considered prior to surgery. The patient should have, at a minimum, a life expectancy of 5 years, and the surgical risk of stroke and/or death should be less than 6%. Carotid endarterectomy is not beneficial for symptomatic carotid stenosis less than 50% and should not be considered in these patients. 

In models of MND, therapeutic manipulations, manipulation of expression of selected genes in specific cell populations [15, 16], creation of chimeric animals to test whether abnormalities are cell autonomous [17], administration of trophic factors to prevent trophic cell death [18-20] and testing of a variety of drug therapies [21-24] have been used to try to ameliorate phenotypes and thus provide insights into disease mechanisms and potential treatment strategies [1, 3, 4, 15, 25, 26]. Results of these studies are being used to design novel therapies to be tested in clinical trials in humans. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

Prostatic cancer In clinical trials involving 350 patients with metastatic prostatic cancer, 11 deaths were reported within 2 weeks of starting high-dose ketoconazole (1200 mg/day). It is not known whether death was related to therapy. High ketoconazole doses are known to suppress adrenal corticosteroid secretion. Hypersensitivity reactions Anaphylaxis occurs rarely after the first dose. Hypersensitivity reactions, including urticaria, have been reported. 

ALS, as already discussed, is a condition characterized by degeneration of the spinal and brainstem motor neurons, resulting in muscle wasting and eventually death. It affects approximately 70000 people worldwide. Several neurotrophic factors known to positively influence motor neurons in vitro and/or in vivo (Table 7.11) have or are being assessed in clinical trials as therapeutic agents for ALS. 

In clinical trials the cumulative risk of death 35 days after starting treatment was 9% in the lepirudin-treated patients, compared with 18% in historical controls cumulative risk of new thromboembolic complications was 6% with lepirudin and 22% in historical controls... 

Tolrestat was withdrawn because of deaths from fatal hepatic necrosis (3) and poor efficacy in clinical trials. Sorbinil was withdrawn because of hypersensitivity reactions in more than 10% of patients. 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

Other causes for failure of gene therapy in clinical trials up to now include short-lasting therapeutic effect triggering of host s immune response mainly against viral vectors problems with viral vectors, such as treatment of patients with SCID, which caused the development of complications, leading to death multigenic disorders, such as heart conditions, Alzheimer s disease, arthritis, and diabetes. 

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