Guidance

Recommendations from the independent Expert Advisory Group on the use of Paclitaxel Drug Coated Balloons (DCBs) and Drug Eluting Stents (DESs) to the MHRA

Updated 18 February 2021

Recommendations from the independent Expert Advisory Group on the use of Paclitaxel Drug Coated Balloons (DCBs) and Drug Eluting Stents (DESs) to the MHRA

1. Executive Summary

The meta-analysis of randomised controlled trials (RCTs) by Katsanos et al on the use of paclitaxel coated/eluting devices (balloons and stents) in the femoral and/or popliteal arteries showed statistically significant increased all-cause mortality from 2 to 5 years post treatment compared with patients treated with plain balloons or bare-metal stents. These findings raised significant concerns on their use in clinical practice and clinical trials.

The independent Paclitaxel Expert Advisory Group (EAG) has been established with two main objectives: 1. to review the relationship between the clinical use of paclitaxel coated/eluting devices and increased mortality; 2. to inform the MHRA on the benefit/risk profile of the clinical use of paclitaxel-coated/eluting devices and to provide recommendations to MHRA on the benefit/risks of the use of these devices in such procedures.

The EAG review concluded that the statistical analysis in the Katsanos’ paper is robust. There is a possible dose dependent effect of the use of paclitaxel coated/eluting devices on mortality although no scientific or clinical explanation is currently available. There are some established causal links between multiple factors and mortality, but the association of increased mortality and the use of paclitaxel coated/eluting devices is established by RCTs which control for confounding in known factors. There is no evidence to suggest that confounding persisted within these studies. Current knowledge gaps include dose-time relationship, outcomes of paclitaxel coated balloons versus paclitaxel eluting stents, patient factors, effect on patients with claudication compared with those with critical limb ischaemia, peerreviewed publication of commercial evidence, mechanistic explanation, and biological evidence.

Following risk-benefit assessments based on current Level 1 evidence, the EAG recommended withholding the use of paclitaxel coated/eluting devices from routine clinical use in patients with intermittent claudication. The devices may still be considered in patients with critical limb ischaemia (CLI) taking NICE Guidance into consideration in conjunction with appropriate informed consent and an enhanced patient follow-up. Formal post marketing long-term surveillance is essential through high quality registries including an endpoint of all-cause mortality.

In terms of future evidence and evaluation, the EAG concluded that paclitaxel coated/eluting devices may still be considered a treatment option within ethically approved trials following appropriate informed consent. In particular, currently suspended RCTs involving patients with CLI should consider resumption in recruitment.

Ongoing and completed trials that have reported results from one or two-year followup should continue or reopen patient follow-up to establish the longer-term mortality status of all patients, up to at least 5 years post-treatment. Future research is recommended to evaluate the causal relationship between paclitaxel coated/eluting devices and mortality including a mechanistic scientifically plausible explanation(s) and the clinical relevance. All approved trials should be submitted for peer review publication regardless of outcome.

The EAG strongly encouraged a collaborative approach among regulatory bodies, trial Data Monitoring Committees and other relevant multidisciplinary groups. An ongoing review of upcoming Level 1 evidence is essential for safe and clinically appropriate use of paclitaxel and other newer drug coated/eluting devices. The current European regulatory classification of drug coated/eluting technologies should be reviewed with a view to enhancing the extent of risk/benefit assessment of the drug in its device-related application, towards that required for medicinal products.

2. Expert advisory group (EAG) membership

Daniel Carradice, MB ChB FRCS, MD(H), PGD Health Econ, PGC Med US (D)

  • Senior Lecturer and Honorary Consultant Vascular and Endovascular Surgeon, Hull York Medical School and Hull University Teaching Hospitals NHS Trust

Ian Chetter, MB ChB FRCS MD, PGD Clin Edu, PGC Med US (D)

  • Professor of Surgery at Hull York Medical School and Honorary Consultant Vascular Surgeon at Hull University Teaching Hospitals NHS Trust

  • Chair Research Committee, Vascular Society GB&I

  • Royal College of Surgeons Surgical Specialty Lead, Vascular Surgery Research

Trevor Cleveland, BMedSci BM BS, FRCS FRCR

  • Consultant Vascular Radiologist and Honorary Senior Lecturer, Sheffield Teaching Hospital

  • President, British Society of Interventional Radiologists

David Flowers, MB BCh BSc FRCR EBIR

  • Consultant Interventional Radiologist, Portsmouth Hospital NHS Trust

Simon McPherson, MBBS BSc, MRCP FRCR EBIR

  • Consultant Interventional Radiologist, Leeds Teaching Hospitals NHS Trust

Iain Robertson, MB ChB, MRCP FRCR EBIR

  • Consultant Interventional Radiologist, Greater Glasgow & Clyde NHS

  • Chair of Scottish Health Technologies Group

  • Devices Expert Advisory Committee

Teik Choon See (Chair), MB BCh BAO, FRCS FRCR FBIR

  • Consultant Interventional Radiologist, Cambridge University Hospitals NHS Foundation Trust

  • Chair of Safety & Quality Committee, BSIR

  • National Patient Safety Advisor, Royal College of Radiologists

The EAG also received expert advisory support from MHRA’s Expert Statistical Assessor and Toxicology Assessor.

3. EAG terms of reference