Fda Perspective on Study Design for Therapies for Severe Sepsis

The Food and Drug Administration (FDA) is mandated by law to determine that approved drugs or biological agents are both safe and effective for their intended use. To this end the FDA assesses both the bene~ts and risks of investigational products before approving them for marketing. Products are approved by FDA only when the bene~ts outweigh the risks associated with therapy. The greater the risks associated with a product, the greater the bene~ts must be for the FDA to deem the product safe and effective. In conditions associated with high mortality rates, the gold standard for clinical bene~t is improved survival. For the treatment of severe sepsis for example, a disease typically associated with crude mortality rates of 30% to 40%, mortality is clearly a clinically meaningful and unambiguous primary endpoint, and is the optimal and appropriate endpoint for the study of agents for sepsis. In some serious conditions other than severe sepsis, clinical outcomes other than survival exist that may confer clinical bene~t to the patient or targeted population. Patients with severe relapsing-remitting multiple sclerosis, for example, not only have a substantially greater risk of death but also of serious disability and frequent relapse because of their condition. Agents that lessen a patient’s risk of progression to disability or decrease the rate of relapse have been approved by the agency for this indication, even though mortality rates have not been demonstrated to be improved with therapy, because the risks of therapy with these agent’s are outweighed by the signi~cant bene~ts patients receive. For agents meant to provide clinical bene~t other than increased survival to patients suffering from conditions associated with high mortality, the following question might be asked to better assess the agents risks and bene~ts of therapy: “Does giving ‘X’ drug/biologic producing a ‘Y’ outcome and showing no effect on mortality-provide a meaningful clinical bene~t to patients”? For agents that may cause an adverse effect on mortality in patients with conditions associated with high mortality rates, (e.g., a systemic immunomodulatory agent or an agent that acts as a vasoconstrictor for patients with severe sepsis) signi~cant and substantial clinical bene~ts must be present to outweigh possible risks. Given our generally poor understanding of the pathophysiology of acute sepsis, the potential for worsened clinical outcomes following therapy with investigational systemic immunomodulatory agents, and the relatively few irreversible morbidities associated with this condition, even small adverse effects on mortality must be excluded in studies of patients with severe sepsis if the risks and bene~ts of therapy are to be adequately assessed. Agents less likely to have adverse effects on mortality might be reasonably evaluated in studies not powered to exclude small mortality adverse effects. Unfortunately, in the area of severe sepsis/septic shock, much preclinical and clinical data have demonstrated that most immunomodulatory or other systemic therapeutic interventions have the potential to increase mortality even while decreasing some acute in_ammatory morbidities. Thus, for interventional therapies for severe sepsis to establish a primary outcome of a clinical bene~t other than mortality “would require substantial mortality data, and would be little, if any easier, and far less meaningful than demonstrating a mortality bene~t” (1). For these reasons, mortality is the optimal and appropriate endpoint for the study of agents for sepsis. “The timing for measurement of mortality represents a balance between concerns about missing many severe sepsisor treatment related deaths with early measurement or including many non sepsis-related deaths with later measurements. Mortality at 28 days is a reasonable choice since mortality curves in septic populations appear to have an in_ection around 20 days, and after day 28, mortality rates are relatively stable and may largely re_ect underlying disease” [1].