Scientific Advisory Committee on Medical Devices used in the Cardiovascular System Summary of Proceedings January 24, 2020

January 24, 2020

Core committee members: John Ducas (Chair), Anita Asgar, Jillianne Code, Renzo Cecere, Eric Cohen, Barry Rubin, Joaquim Miro, Alan Menkis, Marino Labinaz

Regrets: Brent Mitchell, Chris Feindel, John Webb, Raymond Yee

Guest speakers: Thomas Forbes, Sudhir Nagpal, Dheeraj Rajan, Ahmed Kayssi

Health Canada staff: David Boudreau, Saira David, Kevin Day, Ana Ludke, Ben Elliott, Chris Schmidt, Christine Lefebvre, Daniel Yoon, Despina Miteva, Elaine Wong, Eva McGrath, Fatiha Chellat, Geoffrey Green, Giovanni Di Rienzo, Ian Aldous, Jianming Hao, Karen Kennedy, Lanyi Xu, Maurice Sylvain, Maxime Tondreau, Monica Forero McGrath, Patrick Fandja, Roy Masters, Timao Li, Xiaoli Ma

Opening remarks (David Boudreau)

The Director General of the Medical Devices Directorate (MDD) welcomed all committee members and guest speakers, including new committee member Jillianne Code (patient representative). He introduced the new directorate and its role in overseeing the regulation of medical devices.

He then discussed the importance of SAC-MDUCS and the Medical Devices Action Plan, which was published in December 2018. Finally, he described the overall focus of the meeting:

• understanding the use of paclitaxel drug-coated balloons/stents (PCB/PCS) for treating peripheral arterial disease (PAD) in order to strengthen pre-market evaluation, post-market surveillance and public transparency of information

Review of the agenda and affiliations and interests (John Ducas)

The Chair outlined the meeting agenda and requested declarations of actual or potential conflicts of interest. There were none that restricted SAC-MDUCS members from participating.

Summary of previous advice used and general considerations for the meeting (Kevin Day)

Mr. Day summarized advice received from the previous SAC-MDUCS meeting, including His bundle pacing, labelling considerations, and using the Special Access Program to grant early access to devices. He indicated that the feedback received in this meeting would influence regulatory decisions within Canada.

After the publication of the Katsanos meta-analysis paper, concerns arose about the use of drug-coated balloons (DCBs). Health Canada published a notice on May 9, 2019, about the risk-benefit profile of DCBs and informed patients of the risks. The notice was consistent with subsequent messaging by the Medicines and Healthcare products Regulatory Agency and the United States Food and Drug Administration (U.S. FDA). Up to the date of this meeting, no regulatory agency has withdrawn paclitaxel drug-coated balloons.

In light of this context, the goal of this meeting was to discuss objective evidence and clinical expertise on how to regulate Paclitaxel Coated Devices (PCD) in order to address the outstanding concerns. These concerns largely focused on the observed increase in all-cause mortality associated with paclitaxel DCBs.

Presentation #1: Overview of clinical outcomes associated with paclitaxel DCBs used for the treatment of PAD (Ian Aldous)

Dr. Aldous gave a detailed overview of the clinical outcomes associated with PCD for treating peripheral vascular disease. His timeline of events started with the 2018 publication of the Katsanos meta-analysis paper, and he summarized the Katsanos data.

Dr. Aldous discussed the following letters sent by Health Canada:

• Section 39 letter to current licence holders
• safety alert letter to health care professionals that recommended alternative treatment options

He also discussed the 2019 U.S. FDA panel meeting. The FDA panel had concluded that a mortality signal did exist, though it could not elaborate on whether it was a device-specific effect or a class effect.

He also provided a summary of current devices licensed in Canada and outlined the most current information received from manufacturers.

The discussion that followed mainly focused on how the U.S. FDA and Health Canada shares information, as there had been limited interactions between the 2 regulatory bodies. Also discussed were the benefits of paclitaxel, including symptomatic relief in patients with claudication, and the increased risk of death and signal of increased all-cause-mortality.

Presentation #2: Current clinical practice in the use of DCBs used for the treatment of PAD (Thomas L. Forbes)

Dr. Forbes began his presentation by providing some context around PAD. He noted that the U.S. FDA/Vascular and InterVentional Advances (VIVA) meeting participants looked at patient-specific data around paclitaxel. With additional follow-up data included in the analysis, the late mortality signal was reduced but was still statistically significant.

In the face of this continued paclitaxel uncertainty, Dr. Forbes suggested that research and development within the medical industry would quickly pivot to other drug therapies. He indicated that we should be asking, “Why is there a survival advantage with treatment with a non-coated device (mortality drops to 8.1%)?” In response, he suggested a number of possible explanations, such as additional medical visits, increased likelihood of being on the right medication or other factors like exercise and medical management.

Dr. Forbes also commented on the Katsanos below-the-knee meta-analysis (2020). Paclitaxel was associated with worse outcomes for the composite amputation free survival endpoint (but not individual outcomes (for instance, freedom from all-cause death and major amputation)) at 1 year.

The discussion that followed focused on current clinical practices in Canada for treating PAD in cases of asymptomatic PAD, intermittent claudication and chronic limb-threatening ischemia. Also discussed was how clinical practice for treating PAD has evolved in Canada over the last year and how Canadian clinicians have interpreted the data associated with paclitaxel DCBs. This includes:

• a more selective use of paclitaxel
• improved patient awareness and consent
• critiques of the Katsanos meta-analysis
• hospitals’ interpretation of the Health Canada statement as a recall

Also addressed were the ongoing debates about modifying clinical guidelines for treating PAD. A last discussion point explored relevant clinical associations and working groups that could help to inform Health Canada’s regulatory considerations in this area.

Dr. Forbes advocated for an expanded role for post-market/post-approval registries. There was some support for limiting use of paclitaxel DCBs to patients with more severe disease (critical limb ischemia) and limiting their use for patients with claudication.

Presentation #3: Patient benefit associated with the use of DCB and plain old balloon angioplasty in above-the-knee PAD (Ahmed Kayssi)

Dr. Kayssi began his presentation with the conclusion that while drug-eluting technologies above the knee do result in improved patient benefits, it depends on how we understand those benefits. While the benefits are clear when measured by anatomic criteria, we cannot measure benefits according to clinical outcome criteria because they are not detected in trials.

Dr. Kayssi gave a few explanations for why patient-reported criteria are not more widely used in clinical trials:

• more patients are needed
• we lack robust instruments to measure patient-reported outcomes
• qualitative research is less prominent in medical research

He suggested that clinical trials often do not provide meaningful contributions to patient care. This is due to poor data collection methods, selectively reported publications, inappropriately interpreted results, and poor study design and outcomes.

Dr. Kayssi explained that clinical outcomes are often not given priority in cardiovascular trials because device trials aim to obtain regulatory approval rather than answer clinically relevant questions. Death and amputation are important but insufficient on their own.

Dr. Kayssi also suggested there are no good instruments available to assess patient treatment preferences. Existing quality-of-life instruments are not sensitive enough, though qualitative research on human behaviour may offer more insight in the future. Dr. Kayssi discussed quality-of-life endpoints when assessing the clinical benefits of DCBs (for example, when and how often to measure endpoints and other means of capturing clinical benefits), as most outcomes are poorly specified.

The discussion focused on whether Health Canada appropriately communicated risks following the Katsanos meta-analysis. Also discussed was whether pre-market device trials should require a higher burden of proof, similar to drug trials. In response, some committee members emphasized the differences between drugs and devices, especially around user factors. There are also competing perspectives to consider. For example, patients want new therapies, which can motivate early approval. Specifically, patients who face worse outcomes are also willing to take more risks. This phenomenon aligns with the Health Canada communications, which recommends use for sicker and more high-risk patients (for example, critical limb ischemia populations).

Presentation #4: Clinical expert opinion on appropriate indications for use and labelling requirements for paclitaxel DCBs in treatment of above-the-knee PAD (Sudhir Nagpal)

Dr. Nagpal began his presentation by providing context around peripheral vascular disease claudication and the prevalence of PAD, with reference to the Katsanos paper. He considered circumstances in which the treatment options should be used and relative risks (for example, patients with claudication at high risk of restenosis).

Dr. Nagpal considered whether DCBs were recommended:

• in patients with short life expectancies
• in patients with various conditions (for example, with critical limb ischemia or acute limb ischemia)
• as a re-intervention in patients who failed previous procedures (for example, DCB, percutaneous transluminal angioplasty, drug eluting stents or bare metal stents for in-stent restenosis)

Dr. Napal also addressed whether DCBs should be restricted to a maximum lesion length or have a limit on multiple uses of the subject devices. He also considered whether there are specific considerations for paclitaxel-eluting stents that are significantly different compared to DCBs.

The discussion focused on whether objective evidence was available at the population level to support indications for use and to introduce greater restrictions for limiting use to high-risk populations.

The committee also discussed how labelling changes, public notifications or contraindications in information for use could affect clinical practice. For example, the committee considered whether Health Canada should require manufacturers to update their labelling with revised indications for use or whether clinicians should manage use based on evolving clinical evidence with a broader indication for use on the label. The committee members largely supported clinician management of the use of DCBs.

Presentation #5: Patient perspective, patient preference and informed consent (Jillianne Code)

Dr. Code’s presentation focused on patient communication and informed consent:

• the types and amount of information that is most helpful to patients
• how to communicate effectively with patients about emerging issues
• Health Canada’s role in communication, especially improving communications between clinicians and patients

Dr. Code also considered whether Health Canada should:

• enforce labelling changes as a risk mitigation strategy
• take action to ensure that patients have appropriate access to safe and effective medical devices for treating PAD

The discussion focused on informed consent, sources of information for patients and Health Canada’s role in disseminating information. For example, Health Canada is not responsible for patient duty of care, so the information that Health Canada disseminates cannot be patient-specific.

Also discussed were effective ways of communicating with patients about emerging device-related issues, such as through:

• social media
• letters to their health care professionals
• information sessions and webinars
• patient-led organizations
• family caregivers (who are often present at appointments)

Also discussed were the type and amount of information patients typically want, such as:

• expected level of pain
• impact on quality of life
• “significant” complications
• potential for long-term adverse effects
• whether hospitalization would be required
• whether the proposed treatment could cause harm or death

Presentation #6: Evidentiary requirements for new DCBs (Karen Kennedy and Ben Elliott)

Through this presentation and discussion, Health Canada was seeking to determine the minimum clinical data requirements for future licensing decisions for paclitaxel DCBs and paclitaxel-eluting stents used to treat PAD.

The presenters began by explaining the current expectations of Health Canada. Health Canada expects a 1-year follow-up (minimum) from randomized controlled trial data to license a Class IV DCB or paclitaxel-eluting stent. Traditionally, these trials have been conducted across PAD patients to compare target lesion revascularization (TLR) rates (or a similar metric). These studies typically randomize treatment with the study device with non-drug coated balloon angioplasty. In light of the possibility of a late mortality risk with drug-eluting devices, Health Canada is reconsidering these expectations.

The presenters provided case studies for discussion in an effort to generalize recommendations for pre- and post-market clinical requirements for DCBs and paclitaxel-eluting stents. The committee identified clinically driven target lesion revascularization as a valuable endpoint but irrelevant to patients, while amputation-free survival was considered a good endpoint. The committee primarily recommended staying with a 1-year endpoint with long-term, meta-analysis style follow-up across device classes.

Recommendations for pre-market clinical evidence focused on endpoints, study design, patient populations, control groups and sample sizes. The committee was supportive of requiring Randomized Control Trials for DCBs with primary endpoints at 1 year and follow-up for at least 5 years. Sample size should be powered for a patency endpoint. Consideration should be given to the population studied, acknowledging that critical limb ischemia and claudication are different diseases.

Presentation #7: Requirements for use other than within the superficial femoral artery of DCB/DES (Chris Schmidt and Dheeraj Rajan)

Through this presentation and discussion, Health Canada was seeking to determine the clinical need and risk-benefit profile of paclitaxel DCBs and paclitaxel-eluting stents, specifically those used:

• below the knee
• in the arm (arteriovenous fistula for dialysis patients)
• in other vascular applications in the context of the all-cause-mortality signal identified in patients with PAD who have been treated in the superficial femoral artery

The presenters explained that most of the clinical data and analysis available were generated from treating PAD in the superficial femoral artery. In Canada, DCBs that are indicated for use below the knee or in the arm are Class II devices. They are not required to have a scientific pre-market evaluation of safety and effectiveness. The presenters explained that the clinical data available for these devices is limited.

Discussions focused on the following:

• clinical differences between patients (isolated superficial femoral artery disease or distal/more diffuse disease involving popliteal and infrapopliteal arteries)
• treatment of different patients in Canada (arteriovenous fistula, below-the-knee PAD)
• risk-benefit of treatments (DCB use below the knee and also DCB use in arteriovenous fistula)
• safety and effectiveness of coronary PCBs

Closing remarks and adjournment of meeting (John Ducas)

The Chair provided closing remarks and thanked the committee for their time and insight. Health Canada thanked the committee for their participation. The Chair adjourned the meeting.