Scientific Advisory Committee on Medical Devices used in Cardiovascular Systems - Record of Proceedings - December 10, 2010

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Record of Proceedings

Committee Members Present: John Ducas (Chair), Marino Labinaz, Alan Menkis, Brent Mitchell, Joaquim Miró, Ratika Parkash, Raymond Yee

Regrets: Tofy Mussivand, Nancy Poirier, John Webb

Invited Guest: Olivier Bertrand

Health Canada Representatives:
Office of Science: Larissa Lefebvre, Hripsime Shahbazian
Medical Devices Bureau: Ian Aldous, Kevin Day, Ian Glasgow, Fred Lapner, James McGarrity, Mary Morris, Philip Neufeld, Jason Pearman, Roland Rotter, Maurice Sylvain, KokSwang Tan, Lanyi Xu
Marketed Health Products Directorate: Fannie St.Gelais
Health Products Food Branch Inspectorate: Christopher Rose
Bureau of Cardiology, Allergy and Neurological Sciences: Guy Beaulieu, Xiaobing Guo

Abbreviations used in this record

ACS

acute coronary syndrome

AED

automated external defibrillator

AV

atrioventricular

AVR

aortic valve replacement

CHF

chronic heart failure

CRT

cardiac resynchronization therapy

CO

cardiac output

DEB

drug eluting balloons

DES

drug eluting stents

HIFU

high intensity focused ultrasound

IVS

intravascular ultrasound

LVEF

left ventricle ejection fraction

ICD

implantable cardio defibrillator

IRS

in-stent restenosis

MDB

Medical Devices Bureau

OCT

optical coherence tomography

RCT

randomized clinical trials

SAC

Scientific Advisory Committee

SAP

Special Access Program

1. Opening Remarks and Welcome

The Chair opened the meeting and welcomed the members.

2. Review of the Agenda and Affiliations and Interests Declarations

The agenda was accepted as established. It was noted that during the course of the meeting the agenda might be slightly altered to accommodate members' schedules.
Verbal Affiliations and Interest declarations were completed. Members were asked to disclose any conflicts that may arise as the meeting proceeded.

3. Review and acceptance of the Terms of Reference

The revised Terms of Reference was provided to the members at the last meeting, held on June 1, 2010 to review the administrative changes and to provide comments. The members accepted the revised Terms of Reference as is.

4. Update to SAC-MDUCS on Use of Recommendations Given to Health Canada

A Health Canada representative from the Medical Devices Bureau (MDB) gave a brief update to the members on how their recommendations are used in Health Canada's day to day business.

At the last meeting in the Spring of 2010, the committee discussed some of the diagnostic imaging devices which the Bureau has seen some activity on such as those that image vulnerable plaque. The discussion around the table has been valuable in assessing these technologies when trying to find the balance between benefit and effectiveness.

During the discussion of implantable pulse generators, comments were made about the impact of new features and how they may affect battery life. It was discussed that when a feature is engaged, a display should appear on the monitor that would indicate the impact it would have on the battery's life. As this requires a software change, there has been resistance to introduce this kind of modification for less dramatic changes to battery life. If a change does have a significant impact on the battery life, the Bureau is working to ensure that it is reflected in the label in some manner.

The discussion of the DF4/IS4 leads was valuable with regards to looking at imposing some requirements at the pre-market level, getting clinical data before licensing in cases where there are new clinical implications, and deciding whether there are post-marketing conditions placed on licenses. In some cases bench testing seems to be the most rigorous means of testing the mechanical and electrical integrity of these novel connectors, but confirmatory studies can be done to ensure the leads are functioning as predicted.

At the last meeting there was a discussion on robotic navigation systems that highlighted some safety issues which were raised and the Bureau has been working with manufacturers to address some of these issues.

Another topic discussed was drug eluting stents (DES) and the off-label nature, or all-comers inclusion criterion, of some of the clinical trials. The Bureau is seeing more of these devices and there are several new generation DESs in development. These discussions will help set a good foundation in looking at studies that are all-comer trials as opposed to the more classical vigorous, double-blind, randomised studies with very carefully defined inclusion criteria that Health Canada has reviewed in the past for these types of devices. These discussions will help the Bureau set goals and standards for these clinical trials, including how we will interpret and assess the information compared to the classical on-label randomised controlled studies.

In Spring 2009, the topic of ablation technologies was discussed which included cryo-ablation and High Intensity Focused Ultrasound (HIFU). The Bureau has recently seen some activity with HIFU, albeit for novel use not involving ablation of arrhythmias, however, the discussions will help in the assessment of the technology.

In a subsequent discussion, members were interested in device approval times; why some submissions take longer than others to review (in part related to availability of certain devices on the Canadian market). It was explained that the drug eluting stent reviews take longer because these are combination products that have additional regulatory requirements. Review times for non-combination products are typically within expected 90-day timelines for the initial review, but licensing can take longer based on the need to obtain additional information from the manufacturers. The Bureau tracks the time spent on files and this information is available from performance review reports at the end of each year.

In further discussions, it was noted that the Special Access Process has been discussed by the members on numerous occasions and it is on the agenda for further discussion at this meeting. Members were informed that there is an initiative at the Branch level to have this process addressed. Health Canada appreciates the committee members' input into this discussion.

Dr. Parkash joined the meeting.

Presentations for each topic are available upon request.

5. Introduction of sensors into cardiac resynchronization therapy (CRT) devices for the treatment and optimization of Heart Failure treatment

Discussion Leader: Dr. Mitchell

Dr. Mitchell disclosed his affiliations prior the presentation. He provided a brief overview of use of CRT devices in heart failure treatment.

1. Introduction of sensors into CRT devices for the treatment and optimization of Heart Failure treatment.

Effects of Abnormal Activation Sequences include atrioventricular asynchrony, interventricular asynchrony, intraventricular asynchrony and intramural asynchrony.

There are different methods for the optimization of Abnormal Activation Sequences:

• atrioventricular asynchrony:
  optimal atrioventricular (AV) delay - method of Ritter¹
  Transmitral Doppler for longest AV delay without A-wave truncation
• interventricular / intraventricular asynchrony:
  optimal interventricular delay - method of Soogard²
  Tissue Doppler to minimize regional contraction delay and maximize left ventricle ejection fraction
• intramural asynchrony:
  no solution as yet

Use of these methods would be to mainly optimise CRT with non-responders.

Implantable Monitors are used to predict congestive heart failure (CHF).

1. What types of sensors are expected in the near future associated with CRT devices?
   
   There are number of these monitors being introduced, most developed are those using peak endocardial acceleration (Sorin - CLEAR study), endocardial electrogram (EGM) timings (Guidant, Medtronic, St. Jude) and estimated pulmonary artery diastolic pressure from the right ventricle dP/dT (Medtronic).
   
   Critical considerations for the assessment of safety and effectiveness include blinded adjudication and non-surrogate endpoints for clinical studies, and a clear indication of the expected longevity of the sensor(s).
2. What sensors will provide the best information to get insight into the left ventricle ejection fraction (LVEF), cardiac output, and other clinically significant parameters in order to optimize atrioventricular (AV) and (interventricular) VV delay?
   
   There is no clear evidence of superiority of one sensor over another to date. This will be determined by future observations. It is expected that hemodynamic sensors would better measure the intended purpose of CRT than would electrophysiological sensors because CRT are designed for a hemodynamic endpoint rather then an electrophysiological endpoint. Regardless of the sensor type, key endpoints include hospitalization, survival, and heart failure symptoms.
3. Is optimization for cardiac output (CO) necessarily the best way to determine optimum setting for CRT? What are appropriate endpoints for consideration?
   
   Cardiac output is not being directly measured with any of these. Optimization for CO is not necessarily the best but it is as likely as any other endpoint to be useful in this regard. Other hemodynamic sensors are meant to mirror CO and are easier to measure.
4. With the introduction of the IS-4 leads for CRT that may introduce additional sensors, what risks and benefits could be expected for CRT leads and what incremental risk is acceptable to better manage Heart Failure and CRT optimization?
   
   The major risk of more complex systems (including leads) is a greater risk of failure. The major advantage of more complex systems is the potential for greater patient benefit. The acceptable incremental risk is that it is less than the incremental benefit with respect to the ideal outcomes of mortality, morbidity and cost.

2. In light of the clinical trial results from the Reverse, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT), and the Resynchronization/defibrillation for Advanced Heart Failure Trial (RAFT), what should the indications for use for CRT devices be with respect to patients who are New York Heart Association (NHYA) functional class I and II?

Current indications in Canada are:
Cardiac resynchronization therapy defibrillators (CRT-Ds) are indicated for patients with moderate to severe heart failure (NYHA III/IV) who remain symptomatic despite stable, optimal heart failure drug therapy, and have left ventricular dysfunction (EF less than or equal to (≤) 35%) and QRS duration greater than or equal to (≥) 120 milliseconds (ms).

Results of various studies (REVERSE, REVERSE-EU, and RAFT) were presented and discussed. It was concluded that the expected Canadian Cardiovascular Society (CCS) recommendations would be: "for patients with symptomatic heart failure (NYHA II) who remain symptomatic despite stable, optimal heart failure therapy and have an LVEF ≤ 0.30 and a QRS duration ≥ 120 ms."

In general, demonstration of benefits from device/intervention should be visible in 1year for NYHA III and IV patients.

Dr. Bertrand and Dr. Miro joined the meeting.

6. Drug Eluting Balloons

Discussion Leader: Dr. Bertrand

Dr. Bertrand was invited to this meeting to address the topic of drug eluting balloons (DEBs). The chair asked Dr. Bertrand to introduce himself. He provided a short introduction, indicating he is an Associate-Professor of Medicine at Laval University and Adjunct-Professor at the Department of Mechanical Engineering at McGill University. Dr. Bertrand disclosed his affiliations prior the presentation.

Dr. Bertrand is involved in the VALENTINE Trial. This trial has two parts:

• VALENTINE Trial I - DEB for in-stent restenosis
• VALENTINE Trial II - DEB for de novo lesions

There are certain treatment gaps which the drug-eluting balloon attempts to fill:

1. in-stent restenosis
2. small vessels
3. bifurcations
4. acute myocardial infarctions (AMI)
5. chronic total occlusions (CTO)

All of the companies currently making DEBs are using paclitaxel; however, the excipients which they use differ.

The dose of paclitaxel used on the balloon is currently the same from each company:
3 milligram per square millimeter (mg/mm²).

Dr. Bertrand described minimal drug release during delivery but provided no supportive data with this claim.

He mentioned how the off label use of DEBs in the peripheral arteries may be a possible route into the US market.

DEBs are currently used in Europe for in-stent restenosis and small vessels.

He provided a brief overview of DEB technology and noted that there is only some preliminary clinical data available at this time. He noted that there are number of manufacturers that are developing these devices.

A number of drug eluting balloons (DEB's) have been investigated for stent dilation and angioplasty procedures for treatment of native stenotic and restenosed lesions in peripheral and coronary arteries. Treatment modalities have included stent dilation and angioplasty alone or in combination with stents.

1. Should Health Canada's licensing requirements for safety and effectiveness information more closely resemble those for conventional coronary angioplasty balloons or those required for drug eluting stents (DES)? Angioplasty balloons are currently licensed with bench testing and little to no animal or clinical trial data. New DES applications contain extensive animal and bench testing data and randomized clinical data for about two thousand patients with at least some patients with two year follow-up.
   
   Dr. Bertrand recommended randomized clinical studies for investigation of DEB's with a minimum of 1-year follow-up. Surrogate end-points for the study would include angiographic late loss, intravascular ultrasound (IVUS) and optical coherence tomography (OCT). One-year rather than 6-month follow-up is required to capture all cases of restenosis for DES and DEB's. DEB's should be shown to be at least superior to plain old balloon angioplasty. Some attention may have to be given to the labelling claims to ensure these are consistent with the clinical trials performed. Lastly, Dr. Bertrand recommended that the randomized clinical trials should include 100-200 patients. It was noted that the majority of companies will most likely use registries to capture "real life" data for the DEB niche indications.
2. Should dual antiplatelet therapy (DAPT) be recommended for DEB procedures? If required what dosage schedule and duration can be recommended?
   
   The current recommendation is for 3 months of dual antiplatelet therapy (DAPT - Aspirin and Clopidogrel) after treatment with DEB's. However, 20-25% of patients who are subjected to DEB procedures for in-stent restenosis (IRS) will likely present with an acute coronary syndrome (ACS) necessitating DAPT treatment for a year. There is limited experience with 1 month of ASA and Clopidogrel. It is suspected that many patients, after DEB treatment, will require another year of treatment based on the clinical scenarios they are presented with.
3. How should Health Canada deal with "partner" devices, that is, a drug eluting balloon used to deploy a stent (either a bare metal stents or drug eluting stents or Antibody Coated Stent), particularly when none of the devices shows effectiveness alone and the devices are owned by different companies?
   
   For DEB treatment of IRS or any other indication, randomized studies with surrogate endpoints would be required. Sponsors should clearly discuss the comparators selected. The evolving DES literature should enable clinicians to better determine which controls are best.
   
   Dr. Bertrand indicted that DEB technology is being driven by increased safety with no or minimal loss of efficacy. There is some interest in the use of DEB's in peripheral arteries (local delivery of Paclitaxel to inhibit restenosis during angioplasty of the legs). Products for this indication are available on compassionate release. Companies have not provided much data for efficacy. There is a need for randomized clinical trials (RCT).

References:
Sirolimus-Eluting Stent or Paclitaxel-Eluting Stent vs Balloon Angioplasty for Prevention of Recurrences in Patients With Coronary In-Stent Restenosis: A Randomized Controlled Trial
Adnan Kastrati,
JAMA. 2005;293(2):165-171

Outcome Differences with the Use of Drug-Eluting Stents for the Treatment of In-Stent Restenosis of Bare-Metal Stents Versus Drug-Eluting Stents
Daniel H. Steinberg
Am J Cardiol 2009;103: 491- 495

7. Overview of the Special Access Program

Discussion Leader: Kevin Day (MDB)

The Medical Device Bureau has been looking forward to the SAC-MDUCS member's insight regarding this topic. The SAP is intended for authorizing the sale of an unlicensed medical device to a physician for emergency use or if the conventional therapies have failed, are unavailable or unsuitable. Manufacturers cannot advertise or promote their devices through this program; therefore it is strictly a physician driven program.

An overview of the process and legislative requirements were described. It was noted that the program faces some challenges such as timelines (target review of approximately 3 days), new technologies, rare conditions and the difficultly associated with assessing the safety and effectiveness of the devices with limited clinical data. In addition, there was some discussion with regards to the Regulations, what influences the suitability and availability of technology, how to determine the clinical impact of new features of these devices, and the limited control Health Canada has on regulating the use of reusable equipment. It was emphasized that applications require a specific and well documented rationale to justify authorization through the Special Access Program.

At the last meeting, the committee members highlighted concerns regarding possible misuse of the Special Access Program in certain areas. However, it was acknowledged that the program is beneficial for Canadians. Health Canada's current focus is on assessing incremental changes to currently approved technology and determining if these design changes are sufficient to justify authorization through the Special Access Program.

Currently, if a clinician claims that there is a probable therapeutic benefit of the given device compared to licensed devices and some evidence of safety is available, then generally the claim is accepted unless Health Canada has evidence to the contrary. It should also be noted that once a device has been subjected to the first time review, all subsequent reviews are done at a lower level of scrutiny. Therefore, it is unusual that subsequent reviews would be rejected unless the medical rational provided by the clinician is different than the original reasons the initial authorization was granted.

Health Canada is considering introducing an annual review of devices that have previously been authorized through the SAP to ensure no new technology has come onto the market that fills the same role. Health Canada will work with the manufacturers to encourage licensing in Canada, and obtain some additional clinical data from manufacturers on clinical performance to ensure that the devices are safe and effective.

The Committee Members deliberated on this issue. Most members agreed that the SAP was a great program, however they noted there are some weakness' that need addressing. One particular example was that it allows companies an easy way to avoid licensing their products in Canada. It was agreed that there should be more stringent rules with regards to reporting both positive and adverse events related to the use of these products.

The committee members concluded that the SAP is a good program for truly "special" products; however, it is misused as a means to put products on the shelf. Therefore, it is important to introduce a monitoring process for SAP products to demonstrate proper use and reporting outcomes back to Health Canada.

Further discussion with members to develop a Health Canada approach has been recommended.

8. Sutureless aortic valves

Discussion Leader: Dr. Menkis

Dr. Menkis noted that degenerative and calcified aortic stenosis is the most common form of adult valvular heart disease, and surgical aortic valve replacement (AVR) with the use of extracorporeal circulation (ECC) is currently the method of choice which can be performed at low risk.

At least two new "sutureless" aortic valves are currently undergoing clinical evaluation. These devices consist of bioprosthetic valves contained in self-expanding stents with features that enable the devices to attach to the aortic annulus without sutures. The devices are targeted for patients who require valve replacement but are undergoing a second procedure that requires opening the chest such as implantation of a coronary artery bypass graft. The main benefits are decreased cross-clamp time and decreased total procedure time.

Dr. Menkis provided examples of Sutureless aortic valves:

1. Perceval S bovine pericardial (Sorin, Milan, Italy)
2. 3F Enable equine pericardial (ATS Medical, Minneapolis,Minn. USA)
3. Trilogy Aortic Valve System bovine pericardial (Arbor Surgical Technologies, Irvine, Calif)
4. Endosmart Valve Attachment Ring (VAR) (Endosmart GmbH, Stutensee, Germany)

Older patients with multiple pre-existing 'high -risk' comorbid conditions may benefit from reduced ECC time and thus reduced myocardial ischemia by the use of minimally invasive or interventional aortic valve implantation.

1. Is there a predictive model describing the relationship between cross-clamp time and serious adverse events?
   
   No:
   • Some studies show prolonged cross-clamping as an independent risk for poor outcome
   • There are no trials of slow surgeons versus fast surgeons
   • Surgical misadventure may occur at any speed
   • Meticulous accurate surgery is the common thread for optimal surgical outcome
2. Because of calcification, irregularities and asymmetry, it can be necessary to change to a conventional valve. What additional risks does this delay pose to the patient?
   
   Additional risks include all the efforts to stop one procedure, to start another, and all the time it takes if you decide to undertake to start a sutureless valve procedure. Therefore, this results in longer clamp time and cardiopulmonary bypass time. However, transcatheter valves are deployed on calcium; the valve attaches to the calcium.
3. Due to unacceptable outcomes such as paravalvular leakage, it can be necessary to replace these valves after implantation. How should this be scored in terms of risk and cross-clamp time?
   
   In terms of how to score risk and cross-clamp time, it depends when valve replacement would happen. For example, if it is intraoperative, you can not access paravalvular leak until the patient has come off pump and an echocardiogram is performed. If there is a paravalvular leak, then you must open the aortotomy, access the valve and most likely take it out and put in a conventional one. As a result, you would have added an additional 40 minutes to 1 hour of extra cross clamp time if you are required to go in and take out the valve.
4. Should a randomized clinical trial be required for licensing purposes?
   
   Yes, RCT is recommended.
   
   
5. Should the performance parameters of these devices be compared to other aortic valves or to percutaneous valves?
   
   Performance parameters should be compared to standard aortic valves.
   
   For Sutureless Valves in Isolated Aortic Valve Replacement:
   • Conventional results are excellent
   • Aging population
   • Increased co-morbidities
   • Facilitate less invasive surgery
     
     
   For Sutureless Valves in Complex Cases (non Isolated Valve Replacement):
   • Complex or combined procedures take longer
   • Is there benefit to reducing clamp time by eliminating suture placement?
   • Undetermined
     
     
   In summary:
   • There is merit in reducing clamp and surgery time.
   • AVR component of complex cases can be reduced to less than (<) 20 min
   • More experience with 'stent valves'
   • A transition technology from transcatheter to conventional valve replacement
     
     
   It was recommended that sutureless aortic valves are suitable devices for randomized clinical trials.

9. Human Factor Issues related to cardiovascular medical devices

Discussion Leader: Dr. Ducas

The study of all aspects of the way humans relate to the world around them, with the aim of improving operational performance and safety, through improvement in the experience of the end user relies on:

Ergonomics and Applied Psychology

Through application of an understanding of human factors the design of equipment, systems and working methods will be improved.

Recent attention of Human Factors research for medical devices has led to the creation of a Human Factors Program by the United States Food and Drug Administration (FDA) to ensure that the application of human factors engineering is integrated into the design of new products. Also, Human Factors Engineering standards have been recently created by AAMI (HE75:2009) and IEC/ISO (IEC/ISO 62366) which help to specify how to assess human factors in medical device design and how to integrate users into the design verification and validation processes. Health Canada invites the committee to share any human factors issues that they have encountered or are aware of such that Health Canada's evaluators may better prepare for and review human factors issues related to cardiovascular medical devices. Devices covered may include:

1. automated external defibrillators (AEDs),
2. home use cardiovascular devices (support for IPG/ICD/CRT),
3. interventional cardiology devices,
4. cardiovascular user interfaces/monitors, and
5. surgical implants.

"Medical error" is a preventable adverse effect of care causing death or morbidity thousands of times a year in Canada. A variety of causes include faulty or misused medical devices. It was noted that:

- 1/2 of FDA device recalls are due to design deficiency
- 1/3 of FDA device reports cite use errors

Use error results from:

1. confusing interface between device and user
   • - poor control panel and confusing design
   • - poor instruction manuals or training
2. complex devices interacting with human fatigue/stress and/or environmental noises/distractions

To prevent use errors devices must be designed with the medical user, environment and human stress in mind.

The FDA Center for Devices and Radiological Health (CDRH) Strategic Plan considers to:

• Reducing use errors by
  • - accounting for abilities and limitations of users
  • - understanding and anticipating potential hazards
• Phase 2, 3 and 4 aspects of design development and product lifecycle management

Regulators should consider in the design of a device if the manufacturer took human factors into consideration. This is an integral part of FDA approval documentation:

• - Design
• - Training
• - Ease of use
• - Possibility of human error

Members agreed that training is an important aspect of proper use of a product. Hands on training should be provided in the environment where the product would be used under normal conditions. However training alone will not address all the issues. Training materials are not very applicable to highly complex devices. In addition, members noted that devices should have fail safe features built in to minimize user error.

Dr. Yee left the meeting.

10. Overview of recall procedures

Discussion Leaders: Kevin Day (MDB), Fannie St-Gelais (MHPD), Christopher Rose (Inspectorate)

The committee members have requested that a presentation and discussion on the recall process at the last meeting. Three representatives of Health Canada have provided an overview of various steps of a recall process and their respective roles and responsibilities.

Health Products and Food Branch (HPFB) Inspectorate provided a brief overview of:

• What is a Recall?
• Regulatory Requirements
• Roles and Responsibilities

The Food and Drugs Act grants inspectors the power to enforce the Regulations. The Act provides legislation intended for food, drugs, medical devices, cells / tissues / organs, semen, cosmetics and natural health products

Some of the inspectorate's key activities include pre-market scrutiny (licensing, investigation testing authorization, SAP) and post-market surveillance (establishment licensing, recall monitoring, inspections, compliance verifications, risk communications, investigations).

Marketed Health Products Directorate (MHPD) was established in 2002 to enhance post-market programs for drugs, biologics, natural health products and medical devices. The Directorate is responsible for:

• - Coordination and consistency of post-market surveillance
• - Coordination and consistency of risk communications
  • - including development of standard protocols, for example to prioritize and assess signals
• - Regulatory oversight of advertising

The presenter provided a brief overview of risk communication documents, criteria to post a medical device recall notice on Health Canada's website and how and when to increase outreach of the safety information for Canadian users.

Medical Devices Bureau provided an overview of the regulatory limitations and powers with regards to medical devices licenses (issuing, amending and suspending), clinical trials and special access authorizations. Two examples were provided describing slow and fast response times to recall action.

Members were advised that reporting specific or generic device concerns to Health Canada can be very helpful, especially with recalls. Earlier notification helps in processing applications. It was noted that at times, Health Canada is notified at the same time as a public announcement is made, not before. In other instances, Health Canada cannot share information it has with clinicians due to proprietary information.

11. Next Steps, Closing Remarks, and Adjournment of Meeting

The date for the next meeting was discussed. Members will be canvassed to select a date in May and June 2011. Meeting adjourned.