EMA proposes updated guideline on peripheral arterial occlusive disease treatments

The European Medicines Agency (EMA) on Thursday released a draft guideline on developing drugs to treat peripheral arterial occlusive disease (PAOD) of the lower extremities.

The guideline states that lower extremity ischaemic disease (LEAD) is the most common clinical manifestation of PAOD and is characterized by the obstruction of blood flow within the arteries leading to limb loss or amputation.

The updated document, when adopted, will supersede the current 22-year-old guideline which has been in effect since April 2002. EMA said the goal of the revision is to “explicitly address clinical development of medicinal products intended to treat arterial lower extremity disease, to reflect updates in disease classification and management, including the angiosome concept, but also provide guidance on estimands, definition of clinical endpoints, and cover specific aspects related to the clinical development of advanced medical therapies (ATMPs) in the setting of lower extremity arterial disease.”

EMA announced plans to update the guideline in a 2018 concept paper which stated the agency’s intention to use the Rutherford classification instead of the Fontaine classification to describe the severity of the disease.

The revised guideline outlines the design of clinical studies to measure treatment outcomes, as well as those to measure prevention of the disease progression and prevention of ischemic events.

To assess treatment outcomes, the guideline recommends that sponsors measure improvement in walking using either treadmill testing or a six-Minute Walk Distance Test (6MWT). It also states that studies should also measure pain reduction, the healing of ulcers, and improvement in the quality of life.

EMA said studies should use randomized parallel group, double-blind, placebo-controlled design. The agency recommended the use of placebos for the control group “since suitable reference substances have not yet been established in the symptomatic treatment of intermittent claudication, as well as in more advanced stages of disease.”

Trials without a placebo arm may only be used if the comparator drug “has consistently shown superiority over placebo,” according to the agency.

The guidance said that sponsors should measure the rate of major amputations as a primary endpoint to assess disease progression, which should only count major amputations above the ankle. The study design should be randomized, parallel group and double-blind. Treatment should last for a minimum of 12 months.

The guideline states that the criteria used to diagnose LEAD in patients recruited for clinical trials be “clearly defined.” In addition, it said the “diagnosis, type of occlusive lesion (stenosis, complete block) and its location must be confirmed by objective means.”

EMA noted in the guideline that almost 50% of patients with the most advanced stage of disease have no history of prior LEAD, and patients are more likely to be older and male with pre-existing cardiovascular morbidities and renal failure.

The agency also said all LEAD patients are at increased risk of major adverse cardiovascular events, such as myocardial infarction, stroke, cardiovascular death, amputations, and chronic or acute lower limb ischemia.

EMA is accepting comments on the deadline until 30 April 2025.

EMA guideline

EMA proposes updated guideline on peripheral arterial occlusive disease treatments

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