EMA Updates Clinical Requirements in Adult, Pediatric Heart Failure Trials

The European Medicines Agency released final guidance on the primary and secondary endpoints sponsors should use to evaluate drugs to treat acute heart failure — along with recommendations on designing and conducting such studies in children.

The preferred primary endpoint is mortality — cardiovascular or all-cause — at 30 or 60 days, as the treatment course for AHF is often one week or less. Longer-term outcomes such as mortality at six months or a year may be considered, depending on the pharmacological profile of the drug, the EMA says.

Symptomatic improvement is also a valid primary endpoint. Breathlessness is the most prominent symptom in AHF patients, and improvement can be considered a reasonable endpoint, the agency adds.

The EMA recommends using cardiovascular death as a secondary endpoint when all-cause mortality is the primary endpoint. When shortness of breath is the primary endpoint, the secondary endpoint should be all-cause mortality. Other possible secondary endpoints include duration of hospital stay, worsening heart failure, reduction in ischemic events in patients with AHF due to heart attack or other cardiovascular event and improvement in quality of life.

The guidance is largely unchanged from a 2012 draft. For adults, Phase III trials should be double-blind and randomized, as the absence of double blinding may compromise interpretation, particularly in symptom-based studies where subjective elements may dominate, the EMA says.

Placebo-controlled studies are required if a new treatment is an add-on therapy, belongs to a new therapeutic class or belongs to a class that has not previously been considered for acute heart failure. For active comparator trials, the EMA recommends nitroglycerine or nitroprusside for vasodilators, furosemide for diuretics and dobutamine, alone or in combination with dopamine, for inotropes.

To evaluate safety, databases for each group of patients in a trial should be delineated by indication and should be large enough to exclude a detrimental effect on mortality and morbidity, the guideline says.

Pediatric Studies

For pediatric studies, reduction in all-cause death is the preferred endpoint. All-cause death should not differ much from cardiovascular mortality in this patient population, but it’s important to include sudden death when evaluating mortality, the draft addendum says.

“Time to” events such as duration of stay in an ICU or hospital, time to referral for transplantation and time to transplantation without other adverse events may also be used as measures of efficacy in the pediatric population, the EMA says. Echocardiographic measures of ventricular function, especially left ventricle, may also be used as endpoints.

Because of the difficulty conducting trials on pediatric AHF, sponsors should maximize information from other studies, the EMA says. For example, pharmacokinetic and pharmacodynamic information from adult heart failure studies can help to guide the level of PK information and studies needed in the pediatric population. Exploratory dosage studies may also be required.

Comments on the pediatric addendum are due Nov. 30. The draft is available at www.fdanews.com/06-11-15-Addendum.pdf.  Read the final guideline at www.fdanews.com/06-11-15-Guideline.pdf. — Kellen Owings