EMA updates guideline on peripheral arterial occlusive disease drugs
The European Medicines Agency (EMA) has published a revised guideline on the development of drugs aimed at treating peripheral arterial occlusive disease (PAOD) in the lower extremities. It will take effect on 30 June 2026.The main purpose of this guideline is to provide direction for the development of medicinal products aimed at treating chronic ischemia caused by atherosclerosis in the lower extremities. This guideline does not address acute ischemia or peripheral vascular disorders that are of inflammatory or immunologic origin, such as Buerger’s disease and necrotic vasculitis.
The update will replace the current guideline, which is 24 years old and has been in effect since April 2002. The document incorporates several changes from the draft proposed in October 2024. (RELATED: EMA proposes updated guideline on peripheral arterial occlusive disease, Regulatory Focus 31 October 2024)
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 guideline addresses study design, evaluating symptomatic treatment, assessing disease progression, choosing endpoints, safety considerations, studies in the elderly population, and assessing Advanced Therapy Medicinal Products (ATMPs) treatments for PAOD.
The guidance recommends a randomized, parallel-group, double-blind, placebo-controlled design. An active drug-controlled trial without a placebo arm may only be considered if the comparator drug has consistently demonstrated superiority over the placebo.
Acceptable primary efficacy endpoints include walking capacity, pain control, and wound healing. In studies focused on claudication or muscle pain and cramping, the main symptomatic endpoint should be the distance that a patient can walk. For patients experiencing pain at rest, the primary efficacy endpoint is the relief of that pain while at rest. The guideline said that its essential to demonstrate that the investigational medicinal product does not possess analgesic properties related to its mechanism of action, even though pain reduction might be a secondary effect of its pharmacological activity.
Secondary endpoints should highlight clinically relevant data that support the study's aim. These include walking distance, hemodynamic measures, interventional or surgical procedures, quality of life, and analgesic consumption.
The updated guideline revises the previous draft by including new information in the section on assessing efficacy, particularly regarding the improvement of walking capacity.
The added text states that “the 6MWD [six-minute walk distance test] and treadmill test are not interchangeable and the choice between methodologies should take into account, among other parameters, the studied population in terms of disease stage and concomitant CV conditions, as well as accessibility to the different rehabilitation programs (either supervised treadmill or home-based exercise), especially in global trials, which can all distinctly affect the measured outcomes.”
The section on preventing CV or ischemic events has been revised. The revision states that “all cause mortality can be considered as an efficacy endpoint or as a component of a composite efficacy endpoint.” Previously the text indicated that all-cause mortality or cardiovascular events alone “have rarely been used as a primary efficacy endpoint in prevention trials. However, either all-cause or cardiovascular death has always to be considered as an important component of a composite efficacy endpoint.”
Additional text has been included in the section on general statistical aspects for confirmatory therapeutic studies.
The new text states that “Generally, efforts should be made to collect all relevant data for the primary and important other estimands to minimize the need to rely on untestable assumptions in the analysis and interpretation of the study results. Data obtained after discontinuation of treatment or other intercurrent events are of interest when a treatment-policy strategy is used in the estimand.”
Draft guideline
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