The European Medicines Agency (EMA) on Thursday released new draft guidance for public consultation on the clinical development of new drugs to treat chronic heart failure (CHF).
The new draft is meant to update previous guidance, known as “Note for guidance on clinical investigation of medicinal products for the treatment of cardiac failure,” in order to differentiate the types of heart failure between reduced and preserved ejection fraction, call for companies to include patients that are clinically stable early after hospitalization for heart failure, describe ways to measure morbidity and assess the efficacy criteria and the need for morbidity and mortality trials.
At its outset, EMA said the scope of this guideline, which is open for comments through 31 August, is restricted to the development of treatments of patients with CHF, including those in the post-acute phase of heart failure.
As one of the main goals of any CHF treatment is to improve survival, EMA notes that in terms of assessing the efficacy of such a drug, mortality should be considered as the primary endpoint either alone “or as a component of a composite endpoint in combination with hospitalization for heart failure.”
“Although overall mortality is the preferred endpoint, cardiovascular mortality, alone or as composite endpoint, can also be considered to be the primary mortality endpoint provided that all-cause mortality is assessed as a secondary endpoint,” EMA adds.
The agency also makes clear that mortality/morbidity data should be part of a new treatment’s marketing authorization application, though if the basis for a new treatment’s approval is morbidity data, “mortality data are expected to be available in the database in order to ensure that the cardiovascular safety profile is adequately characterized,” EMA says.
And although EMA acknowledges that several biomarkers (neuroendocrine, renal and cardiac) have shown to be independent predictors of outcome in patients with CHF, biomarkers “cannot be included as primary endpoints in phase III clinical trials in CHF.”
Similarly, changes in hemodynamic parameters “may be useful to elucidate the mode of action and the required dose of a therapeutic agent in early phase studies,” EMA says, but they cannot be used as a primary endpoint in a pivotal trial.
HFrEF vs. HFpEF
Across the spectrum of CHF, EMA notes that patients may either have heart failure with reduced ejection fraction (HFrEF) or heart failure with a moderately reduced or largely preserved ejection fraction (HFpEF).
“The distinction between patients with HFrEF from those with HFpEF is important because they represent groups with different underlying pathophysiologic, haemodynamic and neurohormonal abnormalities, distinctly different clinical characteristics, and dissimilar efficacy of existing therapies,” EMA says.
And although the aims of treatment and assessment of endpoints are not different between these two types of patients, treatments “effective in improving prognosis in HFrEF have not shown a similar effect in patients with HFpEF,” EMA cautions, though “effects on recurrent hospitalisations and/or on functional capacity may play a larger role in the assessment of efficacy in patient with HFpEF but experience so far is limited and this remains subject to further scientific discussion.”
EMA guideline on clinical investigation of medicinal products for the treatment of chronic heart failure