The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the Food and Drug Administration (FDA) in the USA have both recently issued new statements on the use of paclitaxel-eluting devices. While the FDA release preliminary analysis results from their ongoing review of data, the MHRA announced they have formed an independent Expert Advisory Group, which has now “begun the process of reviewing the available, but highly complex information on these medical devices.” Following preliminary analysis, the FDA meanwhile recommend that “alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents should generally be used until additional analysis of the safety signal has been performed.”
MHRA launches Expert Advisory Group
An MHRA press release states, the group is made up of leading UK clinicians from specialist societies, including interventional radiology, vascular surgery and scientists with toxicology, medicines and statistical expertise. The group has been formed in response to recently published findings by Katsanos et al “raising concerns over the use of paclitaxel eluting balloons and stents in the treatment of patients with peripheral arterial disease (PAD) and in particular the femoropopliteal artery in the leg. […] The publication suggests a possible increased mortality rate from 2 up to 5 years in PAD patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents. This is compared to patients treated with non-coated balloons or bare metal stents. A causal relationship for this observation has not been identified and may reflect limitations in the way the data were analysed, but this has yet to be determined.”
The MHRA add, “Patient safety is our highest priority and we take information questioning the safety of any medical device very seriously. Since the publication we have been collecting and analysing information from a range of sources to try to understand the significance of the findings for future patient treatment options.
“The devices in question have valid CE certificates and remain on the UK market. The outcome of our investigation will determine if new advice is required or if we need to undertake any other regulatory action. The Expert Advisory Group has been asked to consider whether the publication’s findings and device-specific clinical study results are statistically robust and whether there is any evidence of a causal relationship between the drug, paclitaxel, and increased mortality.
“There are a number of other publications which put forward different results and opinions taking into account other factors such as the overall health of the patient. To assist them they have been provided with the full spectrum of source material available to MHRA, together with all relevant published information we have gathered. The aim is to provide a greater understanding of the potential benefits and risks to patients and will help to guide any possible future MHRA action. The Expert Advisory Group has agreed to undertake and complete their review, including reporting their findings to MHRA, within the next few months.
“Additionally, we are collaborating with the major clinical and regulatory stakeholders, including the British Society of Interventional Radiology (BSIR), the UK Basil-3 trial and NICE, as well as other European and global regulatory authorities.”
If you are worried that you might be affected by this matter, we advise you to contact your GP or specialist.”
FDA issue updated letter to healthcare providers with preliminary analysis results
The FDA recently released an update to their January letter to healthcare providers, in which the Administration “promised to communicate as new information became available”.
“We have now conducted a preliminary analysis of long-term follow-up data (up to five years in some studies) of the pivotal premarket randomised trials for paclitaxel-coated products indicated for peripheral arterial disease”, the FDA writes. “While the analyses are ongoing, our preliminary review of this data has identified a potentially concerning signal of increased long-term mortality in study subjects treated with paclitaxel-coated products compared to patients treated with uncoated devices. Of the three trials with five-year follow-up data, each showed higher mortality in subjects treated with paclitaxel-coated products than subjects treated with uncoated devices. In total, among the 975 subjects in these three trials, there was an approximately 50% increased risk of mortality in subjects treated with paclitaxel-coated devices versus those treated with control devices (20.1% versus 13.4% crude risk of death at five years).”
The FDA add that these data should be “interpreted with caution for several reasons. First, there is large variability in the risk estimate of mortality due to the limited amount of long-term data. Second, these studies were not originally designed to be pooled, introducing greater uncertainty in the results. Third, the specific cause and mechanism of the increased mortality is unknown.
“Paclitaxel-coated balloons and stents are known to improve blood flow to the legs and decrease the likelihood of repeat procedures to reopen blocked blood vessels. However, because of this concerning safety signal, we believe alternative treatment options should generally be used for most patients while we continue to further evaluate the increased long-term mortality signal and its impact on the overall benefit-risk profile of these devices. The FDA intends to conduct additional analyses to determine whether the benefits continue to outweigh the risks for approved paclitaxel-coated balloons and paclitaxel-eluting stents when used in accordance with their indications for use. The FDA will also evaluate whether these analyses impact the safety of patients treated with these devices for other indications, such as treatment of arteriovenous access stenosis or critical limb ischaemia.”
Because of concerns regarding this issue, the FDA states it will convene an Advisory Committee meeting of the Circulatory System Devices Panel to:
- Facilitate a public, transparent, and unbiased discussion on the presence and magnitude of a long-term mortality signal;
- Discuss plausible reasons, including any potential biological mechanisms, for a long-term mortality signal;
- Re-examine the benefit-risk profile of this group of devices;
- Consider modifications to ongoing and future US clinical trials evaluating devices containing paclitaxel, including added surveillance, updated informed consent, and enhanced adjudication for drug-related adverse events and deaths; and
- Guide other regulatory actions, as needed.
- Further details concerning the timing and location of the Advisory Committee meeting will be announced in the coming weeks.
Based on the preliminary review of available data, provided healthcare professionals with the following recommendations, until further information is available:
- Continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents.
- When making treatment recommendations and as part of the informed consent process, consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.
- Discuss the risks and benefits of all available PAD treatment options with your patients. For most patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents should generally be used until additional analysis of the safety signal has been performed.
- For some individual patients at particularly high risk for restenosis, clinicians may determine that the benefits of using a paclitaxel-coated product may outweigh the risks.
- Ensure patients receive optimal medical therapy for PAD and other cardiovascular risk factors as well as guidance on healthy lifestyles including weight control, smoking cessation, and exercise.
The FDA further continued to recommend that health care providers report any adverse events or suspected adverse events experienced with the use of paclitaxel-coated balloons and paclitaxel-eluting stents. Voluntary reports can be submitted through MedWatch, the FDA Safety Information and Adverse Event Reporting program. Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations. Health care personnel employed by facilities that are subject to the FDA’s user facility reporting requirements should follow the reporting procedures established by their facilities. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.
