The European Medicines Agency (EMA) has released a new draft guideline detailing what information it expects of sponsors developing new therapies to treat acute heart failure (AHF).
The guideline, released 15 October, is intended to fill in gaps in its chronic heart failure guidance, explained EMA.
AHF is composed of what EMA refers to as a "wide spectrum of symptoms and signs, accompanied by hemodynamic abnormalities and neuroendocrine activation that arise secondary to abnormal cardiac function." Its guidance, however, only addresses acute left ventricular and concomitant right and left ventricular failure with or without pre-existing cardiac disease.
Though many aspects of treatment are different and depend on the particular cause of heart failure, EMA explains that there are numerous similarities between therapies which may allow for similar approaches to clinical evaluations. These evaluations will largely depend on how the drug works and what benefits patients can expect to receive.
EMA said sponsors should also take into account several factors it said weigh heavily on the efficacy and outcomes of treatments: systolic blood pressure at admission, renal function and the underlying etiology of the disease.
Because mortality in patients with AHF remains high, EMA said companies should also be prepared to justify endpoints based on a number of factors, including the pharmacological profile and mechanism of action of the drug being studied. For mortality-based endpoints, sponsors should be prepared to look at in-hospital mortality during the index admission or the rate of mortality at 30 days after release from the hospital. Longer outcomes may also be relevant depending upon the drug.
Drugs that improve the symptoms associated with AHF while having no impact on mortality are also acceptable so long as they do not introduce deleterious effects and are carefully assessed at pre-determined time points. The use of composite endpoints is discouraged, but may be acceptable if they consist of objective events from valid composite endpoints and indicate a clear effect. EMA said one instance of this is reduced hospital readmissions for AHF, which could be used to show a therapy is effective over the long term.
A number of secondary endpoints are also highlighted by EMA as being useful, including cardiac and non-cardiac deaths, hospitalization, days alive and out of the hospital, recurrent ischemic events, hemodynamic measurements, changes in signs of congestion, quality of life measurements, reduction in relevant biomarkers (BNP/NT-pro-BNP), and indices of renal function.
As with all studies, AHF studies are expected to be double-blind and randomized. New therapies are expected to be placebo-controlled, while follow-on therapies should test against an active comparator-typically the best-in-class therapy at the optimized dose.
Sponsors should also be wary of potential safety issues. EMA said sponsors should be particularly wary of sudden death and other mortality issues, hemodynamic effects (tachycardia, hypotensions, etc), cardiac events (myocardial injuries) and renal function. Special attention should be paid to elderly patients and those with other health concerns, such as diabetes or hepatic disease.
Comments on the draft guidance are due on 15 April 2013.