MINUTES - West Nile Virus Teleconference with Cell, Tissue and Organ Establishments

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Contact : CERB/CBE

Tuesday June 15, 2004
12:00 Noon to 2:00 PM EDT
Building #6, Room 2445, Tunney's Pasture, Ottawa

List of Participants

Health Canada
Francisca Agbanyo, Chair
Bill Casley
Mike Drebot
Liz Anne Gillham-Eisen
Sharon Mullin
Huixin Yang

Ontario
Tracy Carr
Debbie Gaskin
Cameron Guest
Tony Mazulli
Karam Ramotar
John Saldanha
Tom Walker
Corinne Weernick

New Brunswick
Mary Lee-Hebert
Ann Secord

Nova Scotia
Kevin Forward
Jim Mohr

Manitoba
Kevin Russell

Saskatchewan
Tracy Brand

Alberta
Julie Fox
Jonathan Lakey
Bonita Lee
Christina Rogers

Québec
Dana Baran
Hughes Charest
Marc Germain
Suzanne Remy
Marie St. Louis

British Columbia
Paul Dubord (partial)
Dermot Kelly
Muhammad Morshed

Artus
Nabil Chilazi
Dr. Marcus (Hamburg)

Agenda Item 1. Introductions

The Chair welcomed participants to the teleconference and a roll call was taken.

Agenda Item 2. Approval of Agenda

The Agenda was approved.

Agenda Item 3. Meeting Objectives

The Chair informed participants that in May 2003, Health Canada issued a letter to establishments involved in handling Cells, Tissues and Organs (CTOs) for transplantation, advising them to test their donors for WNV where operational feasible and provided guidance on various options, which included Investigational Testing Applications and Special Access Authorization for commercial or in-house tests. Health Canada subsequently hosted a WNV workshop in February 2004, to review establishments' experience with WNV testing in 2003, and discuss strategies for implementation in 2004. The main objectives of the teleconference are to:

1. Provide a brief update on the WNV workshop;
2. Identify barriers to the implementation of appropriately validated and approved WNV tests; and,
3. Discuss options to facilitate WNV testing in 2004.

It was noted, that as the regulator, Health Canada cannot be directly involved in the development of a WNV test. Consequently, Health Canada's role will be to facilitate interactions among the various stakeholders and provide guidance on the regulatory requirements.

Agenda Item 4. Update on WNV Workshop

The Chair provided a brief update on the WNV Workshop with respect to WNV testing. These include the following:

1. Testing of CTO donors was fragmented and inconsistent across Canada
2. Testing of CTO donors was performed primarily at provincial laboratories and hospitals. While serological tests for IgM/IgG were available in all locations, nucleic acid tests (NATs) were only available in some locations. Most of the tests used by these laboratories have not been approved for donor screening by Health Canada. Further, these tests were not validated for cadaveric samples.
3. Canadian Blood Services (CBS) and Héma Québec (HQ) performed testing of some cell/tissue donors under an Investigational Testing authorization.
4. Where WNV testing was performed, it was not always possible to obtain test results for organ donors within appropriate time frames.
5. There was no consensus reached with respect to mandating WNV testing for all CTO donors.
6. There were concerns expressed regarding the performance attributes of the tests employed by various establishments and the lack of standardization.
7. It was recommended that efforts be made to centralize testing in a few selected laboratories across the Country.

The report of the WNV Workshop will be released shortly (already available).

Agenda Item 5. Status of WNV Testing by CTO Establishments

1. Key issues raised with respect to organ donors
   1. There is evidence of WNV transmission through organ transplantation.
   2. While WNV testing was performed by some establishments in 2003, there is a lack of knowledge on the performance attributes of the various WNV tests currently available for testing live and cadaveric donors. Concerns were raised regarding the specificity of the WNV tests, the use of these tests in areas of low prevalence, the implications of false positive results, and the cost of implementation. It was noted that organs were discarded because of false positive serological test results.
   3. For the Artus NAT, which is being used by several establishments, it was noted that there was a high rate of false positives. However, some participants indicated that the rate of false positives was very low given that they had tested over 1500 samples from organ, tissue and cord blood donors with no false positive results. It was noted that a few problems encountered with the Artus test initially may be due to the lack of experience with this new test.
   4. One establishment indicated that they started testing donors for WNV in July 2003 but in the off season, testing was limited to donors who had travelled to WNV endemic areas.
   5. Quebec Transplant has made arrangements with Héma Québec to test their samples for WNV using the Roche Kit.
   6. In some establishments, CTOs were subject to exceptional release if WNV testing was not performed, or if the test results were not available prior to transplantation. However, the value of exceptional release of organs from reactive donors was questioned since some establishments will not accept organs once it has been determined that its donor is positive for WNV. This could potentially reduce the availability of organs for transplantation, particularly if there is a high rate of false positives.
   7. In cases where transplantation occurs before test results are obtained, the results could assist with decision making with respect to patient counseling, monitoring and/or treatment (if available).
2. Key issues raised with respect to tissue donors
   1. Some tissues may not transmit WNV.
   2. There are approximately 6,000 cadaveric tissue donors to 400 to 500 heart-beating organ donors per year in Canada. However, none of the WNV tests are approved by Health Canada for testing cadaveric samples.
   3. Some establishments may be testing cadaveric donors with WNV tests that have not been validated for this purpose. Halifax (and possibly other establishments) has been sending its cadaveric samples to the United States for testing.

Agenda Item 6. Regulatory Requirements for WNV Testing (Should this be mandatory for organ and/or tissue donors)?

Based on the discussions regarding the status of WNV testing in Canada, the following recommendations were made with respect to the regulatory requirements for WNV testing:

1. The participants recommended that the performance characteristics of the WNV tests and the proficiency of testing laboratories across Canada be established before making WNV testing mandatory for organ donors.
2. It was also noted that a risk/ benefit analysis should be performed to ensure that the risk of not testing (i.e., potential for WNV transmission) is greater than the risk of testing (i.e., could result in discarding organs, particularly from false positive donors) before testing is made mandatory for organs donors.
3. With respect to tissues, some participants felt testing should only be made mandatory if there is evidence of WNV transmission through tissues, while others believe testing should be performed until there is evidence that WNV is not transmitted through tissues.
4. It was also noted that it is inappropriate to use most of the tests that are currently available for testing tissue donors because they have not been validated for cadaveric samples. Since it will be problematic to make the testing mandatory for live donors but not cadaveric donors, it was recommended that testing of tissue donors not be made mandatory in the absence of a commercial/approved test for cadaveric donors.
5. With respect to the appropriate tests and testing intervals for live donors who donate repeatedly, it was recommended that a NAT be performed at the time of each donation because, with the exception of semen, the interval between cell/tissue donations is fairly long. In the absence of representatives from the semen establishments, the participants decided not to pursue discussions regarding semen donors. They also questioned the need for testing semen donors in the absence of evidence to show that WNV is transmitted through semen.
6. Health Canada noted that the only way to resolve issues respecting the performance characteristics of the various WNV tests is for establishments to submit their current data on WNV testing to Health Canada for analysis. Health Canada also emphasized the need to perform all future WNV testing under an Investigational Testing (IT) protocol to ensure that data is collected and appropriately analyzed.
   

7. Strategies to Facilitate Implementation of Validated/Approved Tests

Key issues raised include the following:

1. It was clarified that the test recommended by Health Canada for donor screening is a NAT for WNV, not a serological test for WNV antibodies. The serological tests could play a role in follow up.
2. The validation of NATs for cadaveric sample can be quite a challenge. A major problem is inhibition by hemoglobin which can be resolved by extraction and dilution, as well as the use of Internal Controls for monitoring the extraction and amplification steps. Some preliminary data indicates that the sensitivity of cadaveric samples is about 50% less in terms of copies/ml, when compared to samples from live donors. As well, some establishments may choose to declare the results of inhibitory samples invalid (based on their Internal Controls) rather than build additional steps into the testing algorithms to resolve the inhibition.
3. Currently, a well organized national programme is not available to examine proficiency of testing laboratories. It was noted that Health Canada has reference samples that could be used to assess proficiency of laboratories performing WNV tests.
4. With the exception of corneas, the turn-around time for test results is not critical for tissues. Further, a turn-around time of approximately 2 days is feasible and acceptable for cornea donors.

Overall, participants agreed that consolidating testing in a few laboratories across Canada is feasible for tissue donors but not organ donors. A number of participants expressed an interest in performing WNV testing for other establishments:

1. B. Lee from Alberta noted that her laboratory had tested some cadaveric samples using a NASBA assay.
2. Héma Québec has developed an in-house test for cadaveric samples and plans to file an IT application with Health Canada within a couple of weeks. One eye bank in Quebec has already asked HQ to test their donors.
3. Artus indicated that their test has not yet been validated for cadaveric samples but was willing to put a process in place to deal with cadaveric donors and file an IT application with Health Canada.
4. T. Mazulli's laboratory in Toronto is interested in providing testing services to other establishments.
5. It was noted that J. Preiksatis' laboratory in Alberta may also be interested in providing testing services to other establishments.

Other Laboratories: data-spacing-bottom

1. Bonfils laboratories in the Unites States has developed a WNV test for cadaveric blood based on Transcription Mediated Amplification, using the Gen-Probe/Chiron system.
2. ViroMed Laboratories, in the United States, is working on validating a WNV test for cadaveric donors.
3. (Post-teleconference discussion: It was also agreed that Health Canada would organize and institute a proficiency testing scheme for WNV testing laboratories, with Mike Drebot (PPHB) taking the lead and supported by an ad hoc working group consisting of Bill Casley (HPFB) and John Saldanha (CBS). This scheme would use the Health Canada reference reagent prepared by Mike Drebot and currently being characterized in the Saldanha and Casley labs.)

Testing of cadaveric samples could potentially be consolidated in some of these laboratories. Proficiency panels should be put together to facilitate proficiency testing by these laboratories.

With respect to the regulatory requirements, participants were informed that only the manufacturer or importer of the test/test kit is required to file an Investigational Testing (IT) application with Health Canada's Medical Devices Bureau, with the names of all sites involved in the study provided in the application. The IT application review can be completed in 30 days and there is no time limit on the study.

8. Other Issues

Seasonal Testing and other strategies will be discussed during the next teleconference.

9. Action Items

Action Item #1:

Establishments involved in WNV testing should send a summary of their data to Health Canada for analysis to assist with discussions and decision making in the short-term.

Action Item #2:

M. Drebot to circulate articles published in the 1950s on WNV transmission through tissues to participants.

Action Item #3:

F. Agbanyo to send email to participants requesting they confirm their interest in providing testing services to other laboratories.

Action Item #4:

F. Agbanyo to contact T. Kuschak regarding information he was to circulate on behalf of J. Preiksaitis.

Action Item #5:

Medical Devices Bureau to send to participants, the link to the Health Canada Website for test kits approved for donor screening by Health Canada.

Appendix

List Of Laboratories And Contacts For West Nile Virus Nucleic Acid Tests

Facility/Laboratory	Contact Person	Type of Nucleic Acid Test	Validation
HÉMA QUÉBEC 4045, Côte-Vertu Blvd Saint-Laurent, Québec H4R 2W7 Tel: 514-832-5000 Fax: 514-832-1025	Before July 26, 2004 Dr. Louis Thibault, Director, Operational Research Tel: 418-780-4362, ext. 3238 After July 26, 2004 Dr. Marie-Claire Chevrier, Director, Bioproduction Tel: 418-780-4362, ext. 3242	Nested Polymerase Chain Reaction (PCR)	Being validated for cadaveric donors
Department of Microbiology Mount Sinai Hospital 600 University Ave. Toronto, Ontario M5G 1X5	Dr. T. Mazzulli, Deputy Chief Microbiologist Tel: 416-586-4695 Fax: 416-586-8746 Email: tmazzulli@mtsinai.on.ca	Artus Biotech WNV PCR assay	Validated in-house for cadaveric and live donors
Division of Microbiology The Ottawa Hospital 501 Smyth Road Ottawa, Ontario K1H 8L6 Tel: 613-737-8322	Dr. Karam Ramotar, Ph.D Scientist Tel: 613- 737-8899, ext 74748 Fax: 613-737-8324 Email: kramotar@Ottawahospital.on.ca	Artus Real Time PCR Test on a Lightcycler Instrument	Validated for both cadaveric and live donors
Provincial Laboratory for Public Health (Microbiology) 3030 Hospital Drive NW Calgary, Alberta T2N 4W4 Tel: 403- 944-1200 Fax: 403- 270-2216 AND 8440-112 Street, Edmonton, AB T6G 2J2 Tel: 780- 407-7121 Fax: 780- 407-3864	Dr. Peter Tilley Program Leader for West Nile Virus Tel: 403-944-1203 email: p.tilley@provlab.ab.ca Dr. Julie Fox Associate Professor, Microbiology and Infectious Diseases Tel: 403- 944-2724 Fax: 403-283-0142 e-mail: J.Fox@provlab.ab.ca	RealArtTM West Nile LCRT-PCR kit (artus-Biotech USA) In-house NASBA with primers and probes based on Lanciotti primers and probes TaqMan assay	Validation for cadaveric and live donors is ongoing