Scientific Advisory Committee on Medical Devices used in Cardiovascular Systems - Record of Proceedings - March 1, 2019

Core committee members: John Ducas (Chair), Anita Asgar, Renzo Cecere, Eric Cohen, Marino Labinaz, Alan Menkis, Barry Rubin, Raymond Yee
Regrets: Christopher Feindel, Brent Mitchell, John Webb
Invited Guests: Munir Boodhwani, Thomas Forbes, Eric Wasylenko
Health Canada Representatives:
Bureau of Cardiology, Allergy and Neurological Sciences (BCANS, TPD):Émilie Carrier, Timao Li
Bureau of Policy, Science and International Programs: Despina Miteva, Carl Poulin, Andrew Raven,
Director General's Office: John Patrick Stewart
Medical Devices Bureau: Ian Aldous, David Boudreau, Kevin Day, Ben Elliott, Monica Forero, Jianming Hao, Amanda Jones, Karen Kennedy, Mark Korchinski, Roy Masters, Catherine Milley, Chris Schmidt, Peggy Seely, Maurice Sylvain, Lanyi Xu
Marketed Health Products Directorate (MHPD): Patrick Fandja, Dongjiang Song, Elaine Wong, Hui Zheng
Regulatory Operations and Enforcement Branch (ROEB): Barbara Harrison

Abbreviations used in this record:

All cause mortality
AV node:
Atrio-ventricular node
Bundle branch block
Bare metal stent
Congestive Heart Failure
Critical limb ischemia
Cardiac resynchronization therapy
Dual Antiplatelet Therapy
Drug eluting stent
Frozen elephant trunk
His bundle pacing
Health Canada
Healthcare professional
Heart failure
Instructions for Use
Left ventricle
Left bundle branch block
Medical Devices Bureau
Medical Devices Single Audit Program
Multi-point pacing
Mitral regurgitation
Magnetic Resonance Imaging
Mitral valve replacement
No observable adverse effect level
Peripheral artery disease
Pacing Capture Threshold
Percutaneous Coronary Intervention
Right ventricle
Randomized Controlled Trial
Regulatory Decision Summary
Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System
Special Access Program
(MRI) Specific absorption rate
Sinus node dysfunction
Transcatheter aortic valve implantation
Transcatheter aortic valve replacement
Transcatheter mitral valve implantation
Transcatheter mitral valve replacement
Therapeutic Products Directorate
Transesophageal echocardiogram
United States Food and Drug Administration

Presentations are available upon request. The responses outlined below are representative of the discussions/recommendations generated by the committee.

1. Roundtable, Opening Remarks & Welcome

Dr. John Patrick Stewart, Director General, TPD

Dr. Stewart provided opening remarks, introducing TPD's role in overseeing the regulation of medical devices and drugs, and welcomed all committee members and guest speakers. He highlighted the recent media coverage on medical devices and, in particular, the rigorous premarket safety review of medical devices already in place but acknowledged room for improvement. He also commended the committee on serving as a great source of information used to guide the regulation of new medical devices.

Dr. Stewart highlighted the three pillars of the Medical Devices Action Plan and HC's plan to further explore increased patient input.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

David Boudreau, Executive Director, MDB

Dr. John Ducas, Committee Chair

Mr. Boudreau provided an overview of the projects supporting the Medical Devices Action Plan, ranging from regulatory review to international collaboration to increased disclosure and release of information.

Dr. Ducas thanked members for participating in the meeting and confirmed acceptance of the agenda. Committee members, presenters, and observers introduced themselves and provided a verbal update of declarations of affiliations and interests from those initially declared. No declarations required any restrictions on members' participation.

3. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, MDB

Mr. Day provided a summary of past committee discussions and highlighted how information from those discussions influenced medical device decision-making at HC.

Mr. Day thanked the committee for helping shape how HC responds to changes in the medical device field.

4. Discussion on Patient Group Representative

Health Canada employees and Committee members

HC has committed to including patient group representatives on all scientific advisory committees. Draft criteria was discussed for MDUCS's patient group representative. The candidate should be able to share:

Patients should be informed and involved in decision-making but given the complexity of the discussions, representatives require a certain level of understanding of cardiovascular medical devices, physiology, and medical language.

The committee offered several thoughts for HC to consider in the selection process.

5. Ascending Aortic Dissection - Treatment

Presenter: Dr. Munir Boodhwani (Guest speaker)

Dr. Boodhwani introduced himself as a principal investigator of post-market surveillance for the Thoraflex device and an executive member with the Canadian Thoracic Aortic Collaborative. He presented a brief overview of the pathophysiology of Type A dissection and clinical outcomes.

Question Response/Discussion

1. Discuss the available techniques for and surgical approaches to treating Type A dissection and associated morbidity (such as downstream dissection and malperfusion). Include information on the different devices that may be used (e.g. FET devices, hybrid devices). In particular, discuss how the aortic arch is treated when necessary and how the branches radiating from the arch are dealt with.

Standard approach is the hemi-arch replacement of ascending aorta with a sutured Dacron graft. Several alternatives for extended repair are available for more complex disease.

  1. Total arch replacement (useful when arch is abnormal and has an aneurysm or tear) - Device: Sienna Graft with prefabricated branches;
  2. Total arch replacement with FET (to treat ascending aorta and arch and pave the way for future descending aorta treatments) adds a stent graft in the distal aorta to seal the dissection and re-appose the false lumen - Devices: Thoraflex Hybrid and Evita both require wire access from a peripheral access point;
  3. Hemi-arch replacement with open deployment of descending thoracic aortic stent – Devices: off-label thoracic stent grafts with surgical graft;
  4. Total arch replacement with debranching and image guided stent deployment - Device: Lupaie graft or custom grafts, inclusion of branches intended to reduce procedure time; and
  5. Hemi-arch replacement (Dacron graft) with an uncovered distal stent connected to the graft – Device: Ascyrus Medical Dissection Sent (AMDS) does not increase surgical time and provides remodeling benefits downstream (petticoat concept).

2. Are the available devices and techniques sufficient to meet the clinical need? Provide an overview of clinical data for devices to demonstrate this. Or are new devices with specific designs needed? Please discuss any potential device designs that would be beneficial.

Several clinical options are available.

Based on data obtained from the International Registry of Acute Aortic Dissection (IRAD), the 17-year trend shows a reduction in surgical mortality from 30% to 20%. Similarly, data from a Canadian registry (9 centres included into the Canadian Thoracic Aortic Collaborative) reported 123 mortalities from 692 Type A dissection repairs (17.8%), mostly involving cardiac failure, stroke, and hemorrhage. There is also some evidence that centre experience further reduces mortality; data from a systematic review of small case series shows that specialized centres achieve very good outcomes with mortality rates below 10% (mixed data – Type A and aneurysm).

Even following surgical repair, a significant burden of illness exists. Late cumulative mortality rate is estimated at approximately 5% per year. These rates are associated with co-morbidities and issues that remain unaddressed by the surgery: a (distal) false lumen remains in 60 to 90% of patients and substantially increases the risk of aneurysm development; additional distal aortic interventions (occurs in 30% of type A dissection repair survivors) are often complex and carry significant morbidity and mortality risk.

Beneficial characteristics of new device designs will include quick deployment, ability to secure hemostasis, avoiding reliance on peripheral artery access, maintenance of branch vessel perfusion, adaptation to different sizes and anatomical configurations, ability to be customized, and a short learning curve.

3. Given the challenges with studying devices in this space, large randomized trials are not typically performed. This makes assessing the clinical data for a new device challenging for regulators. Can recommendations be made for the amount and type of clinical data HC should require for new device licence applications?

Significant challenges prevent the study of the safety and effectiveness of these devices: acute, middle of the night events; large variability in anatomic presentation (highly heterogeneous population); and operator experience has a substantial impact on outcomes. In the absence of data, the use of subject experts for focused evaluations prior to broader approval is suggested. Hubs of expertise (e.g. Canadian Thoracic Group Collaborative) may be leveraged for clinical evaluation. Dr. Boodhwani's group is preparing for the HEADSTART clinical trial whose goal is to study whether standard or extensive approaches should be used. Dr. Boodhwani suggested consulting this group for useful safety and feasibility endpoints. He stressed the importance of introducing these devices in a high volume expert setting prior to wider dissemination.

Dr. Boodhwani was not supportive of (broad) licensure of new devices based on data from a limited number of patients (i.e. 30 patients) as there are alternative devices available. He supported limiting licensing to high volume centres and indicated more robust data were required to balance safety and patient innovation before expanding to lower volume centres with less experience.

5. Would an arch stent to be used in conjunction with replacing the ascending aorta simplify the procedure and improve outcomes (compared to ascending and arch replacement).

(Not directly responded to.)


Dr. Boodhwani indicated that in Canada, patients with Type A dissections are not transferred to expert centres but are handled at the best regional centres accessible. He added that there was value in creating hubs of expertise; while 70% of Canadian cardiac centres are high volume, 30% still suffer from a lack of experience and there is a need to build expertise at these centres.

Dr. Stewart communicated that Vanessa's Law allows HC to apply terms and conditions on a device licence and these more formal authorities may be used to limit initial use to expert centres. However, sufficient real world evidence is needed to support their safe and effective use. He suggested that another alternative could be a clinician driven trial.

Key Messages / Evaluator Summary
Standard of care for Type A dissection, and CCS and vascular surgery society position statement

The standard of care is surgical repair. Based on expert consensus, extensive surgical repair (beyond conventional) is indicated when there is a tear in the arch or for significant aneurysm disease of the arch (occurs in a minor proportion of patients). It is reasonable to consider extended repair in patients with distal disease or malperfusion, young patients, patients without connective tissue disorders or a high risk subset, and situations in which surgical safety is not compromised.

Risks of surgical repair

Risks associated with surgical repair include aortic rupture, involvement of branch vessels (coronary and cerebral arteries), cardiac tamponade, challenges accessing peripheral arteries for cardio-pulmonary bypass (as those arteries are often involved), time required to induce hypothermic cardiac arrest contributes to hypoperfusion and places organs at risk, reconstruction challenges in damaged tissues, long procedure duration (6 to 12 hrs), and hemorrhage. Additional patient specific risks to be considered include pre-existing co-morbidities (diabetes, stroke, hypertension) that increase surgical risk, shock, malperfusion, dynamic disease (substantial changes in a short time), and fragile tissues.

Comparator devices

Question #1 provided a good summary of available comparator devices.

6. SAP Authorization of Devices for First-in-human or Early Developmental Use

Presenters: Dr. Anita Asgar (Committee member), and Dr. Eric Wasylenko (Guest speaker)

Clinical Case Study

Dr. Asgar described a clinical case she was involved in that required authorization through the Special Access Program for a first/second-in-human TMVI heart valve, for which limited pre-clinical information was available. She presented a timeline of the patient's condition, her clinical experience with the FIH mitral valve, and the health outcomes from its use.

Clinical Ethics

Dr. Wasylenko introduced himself and indicated that he had no conflicts of interest to declare. He also acknowledged that the information he presents has been adapted from other organizations he has worked with; he chairs the ethics consultative group for the Public Health Agency of Canada.

Dr. Wasylenko presented the ethical considerations involved in physician decision-making, including attitudes towards health outcomes. His presentation also delved into the risk matrix approach and factors to ensure that decision-making is performed ethically, including the influence of physicians and the need to balance a patient's autonomy to make an informed decision with the duty to provide benefit.

He described the risk matrix approach and presented five considerations to help ensure that health decision- making is insightful and ethically done well:

  1. Vulnerability of the patient due to multiple potential coercive forces (hope, family pressures, bravery and courageousness, physician-patient relationships), while patient autonomy should also be respected.
  2. Balancing of respect for a patient's autonomous choosing vs. fulfilling the professed duty of a clinician to provide benefit. There is a place for benign paternalism to have some influence, particularly when decisions need to be made outside of normal circumstances.
  3. Influence of clinicians and health care providers on the patient.
  4. The patient's wants/needs and goals need to be understood and together with the knowledge and experience of the treating clinicians become the agreed-upon Goals of Care. For each patient, the clinician cannot assume that the relative importance of: life meaning; meaning of suffering; attention to quality of life and length of life; symptom abatement; and support of functional capability is the same for each individual patient.
  5. Safeguards help navigate issues and may include: assurance that goals of care conversations are skillfully had; inclusion of relevant people within the patient's circle; consideration of whether the institution has a decisional collaborator role; establishment of an up-front mechanism for transparent reporting that recognizes unique patient privacy concerns; assurance of availability of clinical supports in the event of device or process failure to minimize and manage unanticipated harms; and, assurance of the availability of an informed substitute decision-maker in case the intervention results in the patient becoming incapable of making an informed decision during the remainder of an episode of care or further care..

Response/Discussion/Handout Information

1. How much weight should be attributed to the patient's condition?

a. Should HC be more lenient in granting authorization in cases where the device may correct a life threatening condition vs. cases where the device may improve the patient's quality of life but not alter the underlying condition? b. Should HC be more lenient in granting authorization in cases where the patient is terminally ill? Would this be different in terminally ill patients for whom life expectancy is very short (< 90 days) compared to a much longer life expectancy (> 1 year)?

Death, for most patients may not be the only consideration, or even the most important consideration. Patients' priorities are more relevant and clinicians need to understand them. Thus, it is not clear that additional leniency should be warranted, specifically for interventions that prolong life. The patient must articulate what is important to them. The opportunity for success towards the patients' goals is more relevant; tempered by the risks of new harms being introduced.

People with short life expectancies may still have very important life goals to accomplish in their remaining time, so risk of harm is sometimes best related to chance to accomplish goals, rather than to length of life.

2. How should HC evaluate and weight the expected improvement of the patient's condition without objective clinical data, such as for first in human clinical cases?

This was not directly discussed. In the early stages of "Goals of Care" conversations, goals should be established if the device or therapy fails. Open conversations should occur between the clinician and the patient about the known risks and benefits.

3. How much consideration should be given to the patient's and the physician's willingness to accept risk? If both the patient and the physician understand the risks and are willing to accept them, in what cases might HC still refuse access? Given high levels of uncertainty, how can patient informed consent be obtained?

Risk tolerance was discussed more generally in the context of no intervention, which may or may not result in a worse patient outcome (based on "Goals of Care"). It was suggested to assess differences between the patient's risk tolerance and that of the physician (i.e., a high-risk consequence, including death, will be weighed differently by each player in the decision-making process in proportion to the chance of the event occurring); considering views of other key clinical team members: watch for intentional or unintentional coercive influences; and, consider whether benign paternalism or autonomous patient choosing is at play.

4. Are some types of incomplete verification/validation testing more acceptable than others (e.g. biocompatibility, animal testing, clinical studies, cadaver implantation, sterilization validation, fatigue testing)? What if testing is complete, but the sample size is very small? At what stage in development of a device should HC permit its use in humans?

Our standards (complete testing cycle) should usually not be breached. But some would argue they can be occasionally breached after very careful deliberation, and depending on the consequences of not proceeding, the risks of doing nothing, the potential for coercive influences inappropriately guiding the patient or clinician or institution, the degree of displayed wisdom involved in the informing and deciding, and the assurance of availability of excellent and immediate palliative measures if the device fails.

It is of personal view that policy should not be completely rigid, but that an intentional and well-considered breach that holds potentially great risk must be held to a very high standard of decision-making, oversight and publicity.

5. How important is it that a viable bailout option be available?

When a risky surgery is considered, the clinician/team must have a bailout, as well as alternative options if that does not work.

However, to the degree that an alternative option is really a faint-hope last resort towards an intended goal, the existence of a bailout option may not be a requirement so long as there is an adequate and expert palliative treatment option readily available.

6. If there are negative outcomes associated with the use of a device early on in development, should HC communicate these negative results publicly? If yes, how would you recommend this be done in terms of what information should be provided and where should it be communicated?

There is a special duty to report these negative results. It was not clear how this might be done, but HC was encouraged to consider this for future cases. See discussion notes below.


Case Study – SAP Decision Making Process

Mr. Day indicated that for the case study discussed, limited information was provided. Animal studies showed some negative outcomes, but the manufacturer rationalized those by citing physiological/species differences. Normally, HC would prefer to have all testing completed before first use in humans. He indicated there were many conversations with the requesting physician and as a result, everyone involved felt adequately informed. In addition, he indicated that the HC team was ultimately pleased that sufficient time was taken to review the case completely and thoughtfully.

Dr. Asgar stated that several companies did not allow access to devices that were under development and in early clinical testing. Her team also considered an alternative device, but the manufacturer did not permit its use in this patient.

Dr. Stewart shared that these situations are challenging for HC, as some level of clinical experience is needed for Special Access Program authorization, but in this case, all the relevant criteria were met. However, FIH is an area where HC is reluctant to approve because the patient is vulnerable, and there is limited information on the device.

It was noted that HC does not play a role in the clinician-patient relationship. As part of the SAP application process, HC requests the clinician's attestation that the patient has been adequately informed, and that the clinical decision maximizes patient safety.

It was further noted that HC was concurrently reviewing another SAP request for the same device.

Reporting of SAP Outcomes by HC

Mr. Day explained that HC cannot advocate for a specific device and asked the committee to comment on when and how HC should share SAP information with others. Dr. Wasylenko suggested that the publication of findings should be transparent so that everyone becomes part of the knowledge base and sufficient context must be provided as well. The committee generally agreed HC had a duty to publicize information on SAP outcomes as it could impact future decisions, although it was acknowledged that information was inherently unbalanced. In addition, the committee was supportive of asking clinicians to report on outcomes, particularly for FIH.

Dr. Stewart clarified that the purpose of SAP is to allow access to unapproved therapies. HC wants follow up from clinicians but they have historically shared little information after the requirement to provide reports was removed. Incident report forms are now available online and HC reviews incidents on an ongoing basis. The investigational testing program and future introduction of physician sponsored trials will also be an important and useful method of collecting data.

Right of Access to Devices Early in Development

Dr. Wasylenko indicated that unless the rights are "unassailable", which he considered them not to be, there are always mitigating factors. He suggested that HC ought to make devices available if they would substantially change the trajectory of a patient's life (e.g. live longer or better, or reduce suffering within special safeguards). He also suggested that there may be limits if it is too early in the device lifecycle and/or "outside the bounds" and HC would need criteria to refuse.

It was noted that the committee had not identified or discussed what those bounds/criteria could be. However, the committee agreed that a generic checklist is not applicable to all situations. Similar to the circumstances faced by clinicians, HC must combine the best knowledge and intentions to make a decision and accept its consequences.

Key Messages / Evaluator Summary
Considerations for SAP risk/benefit assessment

Lifespan may not be the most important priority for all SAP patients. The patient's Goals of Care should be given serious consideration in the context of the risk/benefit assessment and adequate safeguards should be in place (e.g. bailouts/alternatives). Evaluators should consider the impact of withholding an intervention and, based on the patient's Goals of Care, whether withholding that intervention could result in a worse patient outcome.

7. Drug Coated Balloon (DCB) – The Paclitaxel Effect

Presenter: Dr. Thomas L. Forbes (Guest speaker)

Dr. Forbes prefaced his presentation by acknowledging that two manufacturers of paclitaxel-coated devices provide financial support to the University of Toronto division in the form of unrestricted education grants, and that he was the national Principal Investigator for a study involving a Cook endograft. He provided some background, described the use of paclitaxel-coated stents and balloons for PAD, and highlighted study findings, including the initial meta-analysis (Katsanos et al., 2018) that reported a dose-dependent increase in ACM following the application of paclitaxel-coated stents and balloons in the femoropopliteal artery. Dr. Forbes also summarized industry and government responses and described the paradigm shift in treating patients with less severe PAD.

Question Response/Discussion

1. Do you and/or the Canadian clinical community believe that this is a true safety signal or that this is a statistical anomaly? If it is felt that this is a true safety signal, can you provide any insights into the mechanism by which Paclitaxel could increase ACM starting around 2-years post procedure?

This finding is not considered a statistical anomaly; additional study and information are required.

Although the mechanism is unclear, some relation to systemic exposure was speculated. Preclinical studies have shown that 10% of the dose is delivered to the lesion, while 90% is lost systemically (balloons). There may also be micro particle embolization of the paclitaxel coating (balloons).

The causes of death in many cases were cardiovascular, which is expected and common in this population. The other causes of death such as infections and pulmonary issues are more concerning.

2. Are there specific steps that you recommend that HC take to further examine the potential link between DCB/DES that have Paclitaxel as the active pharmaceutical ingredient and all-cause death? Is there data that HC should request from manufacturers? Are there studies that should be undertaken to further explore this issue? Should HC reduce, eliminate or alter market access to these devices?

The following steps were recommended: acquire patient specific data (device/dose specific survival curves); explore the cause(s) of death in greater detail; conduct/enlist independent statistical analyses; and form and/or engage with a task force (e.g., Society for Vascular Surgery (SVS), US FDA).

Potential options for HC: take no action but continue to monitor; impose a moratorium until new information is available; or limit use of the device. It was highlighted that the increased mortality signal was primarily seen in patients with only claudication and greater life expectancy. It was further suggested that the selective use in patients with CLI who are at risk of limb loss and have shorter life expectancies is more appropriate. In addition, he stressed that these considerations should be discussed during the patient informed consent process.

3. What are your recommendations in terms of the regulation of other drug coated devices? Might this finding be applicable to other Limus based drugs? Should HC require more long-term data from devices that contain a pharmaceutical ingredient, even if this results in a significant delay in licensing the device in Canada compared to other regulatory jurisdictions?

Approval and availability of devices for patients must be balanced; if 2 to 5-year mortality data were required for licensing, clinicians would not have devices available to treat patients.


Validity of this Safety Signal

During the pre-market review of a paclitaxel-coated balloon, evaluators identified an increase in ACM at 2 years, which was subsequently deemed an anomaly. These clinical data were included in the device labelling.

In discussing challenges with identifying a possible mechanism of action, a wide variety of excipients are used in implicated devices and the drug delivery is quite different between different balloons and between balloons and stents. HC generally believed that the paclitaxel levels patients have been exposed to were below the NOAEL derived from animal studies and that human systemic levels are expected to be undetectable. It was further noted that some stents retain 90% of the drug at 5 years and that mortality rates are similar between balloons and stents at 2 years, while the drug release profiles are very different.

Concerns about the potential cardiotoxicity of anti-tumour drugs related to paclitaxel were raised, as a possible mechanism could involve progression of heart disease. Dr. Forbes indicated the limited data pointed predominantly to coronary-related deaths, and that this likely speaks to the atherosclerotic burden and not toxicity and non-cardiac causes.

As there was no reported safety signal at 1 year, it was very difficult to understand how a drug that is largely cleared within 2 to 3 months could cause issues at 2 to 3 years.

The three studies which showed a difference in ACM at 5 years also showed a difference at 1 year, even though the overall meta-analysis reported no difference at 1 year. It was suggested that radiation toxicity could reflect this pattern. A committee member stated that they would not discount potential cardiotoxicity and highlighted that these patients are fragile and may be more easily affected. They suggested that in response to the negative publicity associated with paclitaxel, companies would likely seek to replace the drug.

Additional Exploratory Work

Mr. Day provided an overview of HC regulatory authority for requesting additional information from manufacturers of licensed devices. He also asked the committee to comment on the scope and type of information HC should focus on, and highlighted the importance of obtaining guidance for regulatory decisions in the short term.

Dr. Forbes indicated that there were opportunities for engaging with others instead of requesting new data.

Altered Regulatory Approach

Mr. Day highlighted that while RCT data show a relationship between paclitaxel coated devices and ACM, some real world evidence refutes this signal. To solve this discrepancy, he asked the committee whether HC should require 2-year data with drug coated devices or rely more on post-market data and real world evidence. Some committee members suggested that HC might not approve a balloon or stent with less than 2-year data given this mortality signal. Mr. Day indicated that HC has historically required 1-year data, and has received 2-year data for some devices. Based on these discussions, he questioned whether 1-year data for CLI indications might be sufficient, and that labelling would need to include conditions. Some committee members indicated they would support a label warning, but asked about options for patients with stable (extreme) claudication. One clinician noted that they routinely use non-coated balloons/stents or perform bypass procedures as options. In addition to label warnings, HC could disseminate a recommendation that clinicians not treat patients with claudication only and limit paclitaxel-coated balloon/stent use to patients with CLI. In addition, manufacturers could be asked to amend the indications for use or provide data to justify use in non-CLI patients. The committee was generally supportive of this approach.

One committee member stated that claudication is a benign disease and many patients will continue to experience symptoms at 5 years unless they stop smoking; he has almost exclusively used stents to treat CLI and almost never used them for claudication only. Therefore, the proposed policy is consistent with current practices.

Key Messages / Evaluator Summary
Safety signal associated with paclitaxel-coated balloons and stents indicated for use in femoro-popliteal arteries

Statistically increased incidence of dose-dependent ACM was observed at 2 and 5 years in a cohort composed primarily of claudication patients (90%). Additional information is required to better understand and validate this safety signal.

Clinical safety data required for new drug eluting stents and balloons

There was no unanimous support for an approach. Some support was given to maintain historical requirement for clinical data to 1 year. Some recommended 2-year data, with a possibility of this 2-year data requirement for an indication specific to claudication.

IFU labelling requirements

Indications for use should be limited to patients with CLI, unless data are provided to demonstrate safety in non-CLI patients.

8. Use of labelling (IFU & Other)

Presenter: Dr. John Ducas (Chair)

Dr. Ducas summarized the recent media attention surrounding medical device adverse events and information that is made available for public consumption. He outlined several possible rationales and discussed how clinicians use labelling, highlighting clinical data from sources such as clinical trials and real world evidence.

Furthermore, he presented a summary of the views and opinions of the Canadian Medical Protective Association concerning potential medical and legal risks associated with "off-label" use, along with recommendations for minimizing clinician liability.

Question Response/Discussion

1. How do clinicians use IFUs for CV and related devices?

Most clinicians do not use IFUs, except to answer technical questions. Committee members did not see a need to review IFUs, as they lag for scientific evidence, may slow progress, and prevent open communication about the use of the device.

2. What other groups use IFUs (e.g. CADTH, provincial funding agencies)?

Hospital and regional administrators may use IFUs for a Request for Proposal (RFP) when purchasing medical devices. Junior residents/trainees may also use them for procedural guidance and device knowledge.

3. What impact do HC proposed changes (e.g. a change to indications) have on clinical use? Distinguish between personal clinician choice (based on experience and knowledge) from other influences (institutional, patient-driven, other).

HC-proposed IFU changes to indications have variable impact on clinical use; other contributing factors include clinician personal choice, patient factors, and institutional requirements. Device sales representatives are only at liberty to discuss approved indications, although they routinely see off-label use.

4. Do patients ask committee members for device IFUs/printed information? Is there a need for more patient-directed labelling for cardiovascular devices, which more clearly outline device-specific clinical data/outcomes/key risks?


Based on current media influences, medical and legal pressures, and societal and ethical issues, patient centred information was strongly supported.

5. While changes to IFU requirements may need international partner/stakeholder agreement, are committee members supportive of HC publishing device-specific clinical data/outcomes/key risks on the HC website?

The committee was supportive of HC publication of device specific clinical data/outcomes/key risks on the HC website.

6. What might be some legal implications of HC communicating potential device risks/benefits to patients?

Legal implications for HC were considered minimal, as it is a patient's right to informed consent. A patient may sue a doctor for lack of consent, and/or incompetence that directly caused harm. Information given to patients should have no effect on either.



Some device IFUs are intended specifically for patients. All patients who receive a pacemaker also receive a document/manual that is comparable to an IFU, which is written in plain language. Most major device companies hold clinicians to standards, particularly for complex devices; companies require clinicians to review and sign off on device IFUs as independent operators. It was clarified that "off-label" means that use was not included in the studied endpoint but does not mean that the "off-label" use was investigated and that use failed, as would be the case with a contraindication.

HC Device Specific External Communications

HC currently sends risk communications in the form of "Infowatch" and "Dear Healthcare Professional" letters, but acknowledged that getting information to HCPs remains an issue. HC is currently assessing whether those risk communications are efficient tools. A committee member indicated that harms reported at scientific meetings are very impactful; however, "Dear Doctor", Black Box Warnings, and Public Health Advisories have variable effectiveness.

Another member suggested that the IFU is the worst vehicle for disseminating new information, and that another approach should be sought.

Mr. Day described RDSs and explained that they could be promoted more actively by HC. The committee indicated that patients would most likely not understand the RDS and non-technical language needed to be used for a patient audience.

A committee member indicated that companies would likely not provide the same information and the RDS would at least inform clinicians of reported data and outcomes. They also suggested that clinicians would be far more likely to read the RDS than the IFU, and that a simple patient summary could be added for the public. There was general agreement and the committee thought the RDS was a good means to facilitate patient engagement.

One member added that the onus was not on HC to provide that information to patients; by Canadian case law, physicians are required to obtain informed consent and explain every likely complication, whether serious or not serious, and all potentially life-threatening complications, even if they are extremely rare.

Key Messages / Evaluator Summary
Users of medical device IFUs

For high-risk cardiovascular medical devices, hospital and regional administrators, junior residents and trainees. (not physicians)

Users of RDSs

Clinicians (reported outcomes)

9. Acceptable PCT Change in LV vs. RV

Presenter: Dr. Ben Elliott (Senior Scientific Evaluator, MDB)

Dr. Elliott presented the proposed HC approach to MR-Conditional labelling for pacing systems that are more susceptible to RF-induced lead heating than previously licensed MR-Conditional systems. As elevated lead temperature may be associated with myocardial damage (including fibrosis) and increased pacing capture thresholds (PCTs), HC seeks to mitigate MRI-related risk (i.e. reduced battery life and loss of capture) by introducing limits on MRI scan conditions for patients implanted with pacing systems where MRI scan-induced heating may lead to PCT increase.

Question Response/Discussion

1. Are members of the committee comfortable with Health Canada's regulatory approach for PCT change limits for LV leads and RV leads as well as other general requirements?

The committee considered the proposed approach and PCT limits to be reasonable.

2. Are members of the committee comfortable with less stringent PCT change limits for LV leads vs RV leads?

3. Can committee members provide a brief overview on the degree to which MR conditional IPG systems are being allowed in MR scans in Canada?

(Not directly responded to.)

Key Messages / Evaluator Summary
RV Lead MR-Conditional labelling requirements

MR-conditional labelling of pacing systems where PCT increases <0.5V are acceptable.

MR-conditional labelling of pacing systems where PCT increases >0.5V and <1.0V are acceptable, provided that the following additional warning is included:

"There may be up to a 1% risk that an MRI scan will cause right ventricular lead electrode heating, leading to a pacing capture threshold rise of > [worst case PCT as determined by Monte Carlo simulations] V, especially for high RF Power (SAR) scans of the cervical or thoracic regions in patients with high BMI."

Previously accepted LV Lead MR-conditional labelling

MR-conditional labelling of pacing systems where PCT increases of >1.0V and <1.5V are acceptable with a labelling warning similar to that listed above. However, a Pre-scan PCT limit 0.5V lower than that established for the corresponding right-heart leads must be included.

10. His Bundle Pacing

Presenter: Dr. Raymond Yee (Committee member)

Dr. Yee presented on the usage of HBP. He explained that although RV pacing has been the standard treatment for significant bradycardia, there is renewed interest in HBP as it is thought to achieve superior hemodynamic results and patient outcomes. In addition, right sided pacing is known to negatively impact hemodynamics and LV function. He described situations where it could be used and an overview of early attempts.

Question Response/Discussion

1. Discuss the main clinical rationales for HBP.

HBP is more physiologic, simplifies the implant procedure, and decreases hardware and device feature complexity.

2. What specific population would benefit most from the permanent HBP? Are there specific populations that would be at high risk for the HBP?

Any patient that requires ventricular pacing (e.g. fixed AVB, LV systolic dysfunction), but not patients with SND. Dr. Yee commented that there may not be any patient populations that would be at high risk once HBP is chronically reliable. However, he indicated that caution is required for pacer-dependent patients.

3. Compared to traditional electrophysiological therapies, such as cardiac pacing, and cardiac resynchronization therapy, etc., and by considering the anatomical variation of His bundle among the patients, what are the inherent complications associated with the devices and/or procedure? Particularly, discuss the potential risks of lead dislodgement and perforation.

Expected complications include chronic PCT rise and atrial over-sensing (results in non-pacing). Dr. Yee considered dislodgement a lesser issue and added that PCT at <1.5-1.7V was generally acceptable. At >2.0V, however, battery longevity would be impacted.

4. What endpoints need to be assessed in a clinical study for HBP system to demonstrate its safety and effectiveness?

Endpoints should focus on safety and hardware performance (durability, PCTs, and lead electrical values) for at least 12 months. Lead dislodgment and the need for lead system revision may also be considered. A clinical effectiveness endpoint study is not needed for regulatory approval and the medical community will chose or avoid HBP based upon weight of effectiveness, performance and safety evidence.

5. Provide a summary of currently available clinical evidence. Discuss whether the currently available clinical evidence is sufficient to demonstrate the safety and effectiveness of the HBP technique.

Available clinical evidence is limited and of poor quality, but provide some support for safety.

Zanon (Europace 2018; 20:1819) supports the effectiveness of His or Para-His pacing in populations with variable aetiologies (AF ± AVN Abl, VB, SND, CHF), and superiority over RV pacing. While procedure and fluoroscopy times were greater, QRS durations were shorter, and PCTs were reasonable.

Kronborg (2014) compared direct/indirect His pacing with RV septal pacing, and His pacing showed a modest increase in LVEF. Lustgarten (2015) compared HBP vs. RV/LV pacing for CRT. The endpoint was LVEF after 6 months compared to baseline. 21/29 achieved QRS narrowing. In 12 patients, His and BIV had better EF, but His results in EF equivalent to CRT. His was as good when used for CRT, and was simpler and less expensive.

Dr. Yee acknowledged that the medical community remains skeptical that HBP is ready for market release.


Device Safety and Performance

Dr. Yee's response to potential tricuspid damage is that there might be a risk with a stylet driven lead, but less with catheter delivered leads because of the smaller mass of the leads and the path of the lead to the His bundle means the lead would not be sitting on the leaflets. However, he did indicate that tricuspid valve effects are not commonly studied, and suggested they should be.

A committee member added that a tangential His approach may get in the way of tricuspid repair devices, but acknowledged that they have seen many patients with tricuspid regurgitation resulting from leaflets help open by leads. They suggested that the HBP approach would not impact leaflets and could also help these patients. Dr. Yee added that the His approach is on the base of the tricuspid and not on the leaflet.

A question was raised about the potential differences between RV and HBP systems. Dr. Yee indicated that greater battery capacity would be required to overcome potentially elevated PCTs, and better atrial filtering would be required to overcome atrial over-sensing. He also noted that many operators do not fully trust HBP and place a backup lead in the RV to avoid asystole.

Unmet Needs

There are no pacing generators specifically designed for the His bundle.

A question was asked about the impact of anatomic variations of the His bundle. Dr. Yee explained that in a radiologic space, the heart can vary tremendously and no two patients will have the His in the same spot, radiographically. In addition, pathologies and heart rotations influence radiographic His location. He suggested that the ideal device would have a deflectable catheter to find the spot and indicated that some companies are working on that strategy. He added that the location cannot be reached from the coronary sinus.

A question was asked if one would expect a similar CRT responder rate with His pacing. Dr. Yee expected that HBP would improve CRT responder rate, largely because inappropriate LV lead localization would be avoided. However, he indicated His pacing would not help in patients with distal BBB, as the ventricles could not be synchronized.

Key Messages / Evaluator Summary
Indications for direct and indirect HBP

To treat bradycardia associated with HF (to support CRT therapy but not in patients with distal BBB) and AVB requiring ventricular pacing (e.g. fixed AVB, LV systolic dysfunction), but not SND.

Rationale for HBP

Avoids negative consequences of RV pacing (cardiomyopathy, ventricular dis-synchrony) because this approach is physiologic and may avoid tricuspid involvement.

Known adverse effects

Chronic PCT rise

Atrial over-sensing (results in non-pacing)

Lead dislodgement (to a lesser extent)

Clinical endpoints

Safety and hardware performance: durability, PCTs, lead electrical values, lead dislodgement, and lead system revision for at least 12 months.

11. Closing Remarks and Adjournment of Meeting

Dr. John Ducas (Chair)

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

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