Minutes: September 1, 1999 - Expert Advisory Committee on Xenograft Regulation (EAC-XR)

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Committee Members Present:

Dr. Michael Gross, chairperson; Dr. Michele Bailey; Dr. Henry Dinsdale; Dr. Arvind Koshal; Mr. Peter Portlock; Dr. Jutta Preiksaitis; Dr. Bhagirath Singh; Dr. Rosalie Starzomski;

Ad Hoc member:

Professor Tim Caulfield; Dr. Lyne Letourneau; Dr. Stephen McColl.

Health Canada Representatives:

Dr. Robert Peterson; Dr. Keith Bailey, Bureau of Biologics and Radiopharmaceuticals (BBR); Dr. Peter Ganz, BBR; Dr. Doug Kennedy, BBR; Dr. Marian Laderoute, BBR; Dr. Paul Sandstrom, Laboratory Center for Disease Control (LCDC); Ms. Kim Hannah, Bureau of Policy and Coordination (BPC); Mr. George Samiotis, BPC; Mr. Andre La Prairie, BPC; Ms. Lesley A. Way, Legal Services; Ms. Lisa Fudge-Lunetta, Legal Services; Ms. Lauraine Begin, BPC; Ms. Sue-ann Blakely, BPC.

Observer:

Dr. Min Jiang, Bureau of Medical Devices (BMD)

Regrets:

Dr. Francois Auger; Dr. Lorne Babiuk; Dr. Paul Greig.

Opening

The meeting opened with Dr. Peterson, Associate Director General welcoming and thanking the members to this new Expert Advisory Committee on Xenograft Regulation for their willingness to serve on the EAC which followed by a round table of introductions. He provided a brief history of the role and basic functions of external expert advisory committees within the Therapeutic Products Programme (TPP). The members were reminded that they do not represent the particular association that nominated them and that prior to discussions involving confidential information, their security check must be cleared. Conflict of Interest was briefly discussed and members were asked to discuss any concerns they may have prior to meetings. A conflict does not necessarily disqualify a member from the committee however it may limit their participation in providing advise or recommendations from the committee on a particular subject matter.

The meeting was turned over to the chair of the EAC, Dr. Michael Gross. Xenotransplantation and the National Xeno Forum held in November 1997 were briefly discussed. The extreme shortage of organs in Canada and worldwide has been one of the strong driving forces for Xenografts.

Dr. Peterson orientated the members to the TPP describing the mandate of the programme and some of the bureaux which will be closely linked to this EAC-XR. The Organization chart was reviewed and members were invited to visit the Health Canada website to view existing EAC's, Membership, Mandate and Terms of Reference at http://www.hc-sc.gc.ca/hpb-dgps/therapeut go to Advisory Committees. It was emphasized the final responsibility for decision-making lies with TPP.

Ms Lauraine Begin gave an overview of the governing Act and Regulations. The Parliamentary process and time lines of writing and implementing new Regulations was discussed. The committee was provided the definitions of "drugs" and "devices" as well as "sell". The information session explained the changing environment and the proposed future framework for regulating drugs and devices by TPP.

A joint presentation by Ms. Leslie A. Way and Ms. Lisa Fudge-Lunetta gave the committee members an overview of the legal issues associated with the external Expert Advisory Committees. The mandate for all EACs primarily is to provide the programme with advice and recommendations on medical, scientific, ethical and communication issues. The Access to Information Act and liability under this Act was clarified for the members. Conflict of Interest (COI) including the perceived COI was reviewed. It was explained that members perceived as utilizing their position in the furtherance of their private interests, whether financial or otherwise constitutes a conflict. Members will be solicited information on COI prior to future agenda items where appropriate. The general policy of Health Canada is to provide its committee members the necessary protection for indemnification and legal assistance, within the framework and limitations of government policy. The policy applies to advisory committee members who are volunteers or those that are Departmental appointees. Members that participate in debates, panel discussions, interviews etc. outside the Committee must make it clearly understood that they are representing themselves and are not speaking as a Committee member. Regulatory questions that committee members receive should be directed to Health Canada.

Discussion on the Draft Terms of Reference (TOR) for the EAC-XR was deferred until after the meeting. Members were asked to review the TOR and send comments back to the chair and the coordinator for review.
Action: The committee members to comment on the DRAFT Terms of Reference prior to the next meeting.

Standards-Based Regulatory Model for Transplantation was presented to the committee. The traditional Regulatory approach was discussed in terms of the Statue, Regulations, policies and Guidelines. The Standards if referenced in regulation have the force of law, yet are written in comprehensive language, can address current and changing technologies in a timely manner and are built on a consensus principle thereby increasing transparency. An Expert Working Group was established in March 1996 and has created the Draft Canadian General Standard for Tissues and Organs. Several Standard subsets were created such as the Proposed Canadian Standard for Xenotransplantation (PCSX).
The Proposed Canadian Standard for Xenotransplantation is expected to be distributed for general comment within the near future..

Regulatory actions include:

• Notice of Intent
• Notice to hospitals
• Policy on Special Access Program
• Information sheet - Lay version
• Fact Sheet - Xenotransplantation
• National Forum on Xeno published

In progress:

• DRAFT Interim Guidance document - Clinical Trials Involving Xenografts
• Public Involvement Plan

Information regarding Xeno issues can be viewed on the Health Canada Website http://www.hc-sc.gc.ca/hpb-dgps/therapeut go to btox.

Ms. Kim Hannah presented the proposed Public Involvement Plan to the committee members. The Plan encompasses different levels of activities related to the magnitude of different issues to be addressed. The phases of the Public Involvement Plan and Policy development phases were outlined. The Health Monitor survey results were reviewed. Regarding donation, 30% of responses indicate that donors intend to sign there donation card, 50% have already signed their card. 60% of respondents wish to be kept informed and 50% would consider a Xenograft if no human tissue or organ is available. The questionnaire used will be forwarded to the EAC-XR members.

Action: The committee will be sent the Health Monitor Survey questionnaire.

Dr. Peter Ganz updated the committee on the various TPP committees involved in Xenotransplantation issues. The Blood, Tissues, Organs and Xenografts Steering Committee (BTOX-SC) provide advice to the Director General and Programme Management committee regarding policy issues relating to blood, tissues, organs and xenografts. This steering committee has completed several documents relating to Xenotransplantation. The Notice to hospitals: Clinical use of viable animal cells, tissues or organs to treat patients outlines the sponsors responsibility to investigate these procedures only under authorized clinical trials. Sponsors of clinical trials involving Xenografts must send a submission to the TPP for approval before a clinical trial may proceed. Practitioners who may contemplate using the Special Access Programme (SAP) as a mechanism for using xenografts in a transplant procedure should be aware that TPP is not presently in a position to consider applications under SAP for xenografts since risks to third parties cannot be adequately assessed on an urgent basis. The DRAFT Interim Guideline For Clinical Trials Involving Xenografts provides sponsors with the existing policies and guidance in preparation of submissions. The administrative procedures for submissions are referenced such as TPP's policies on Clinical Trial Review and Approval and Preparation of an Application for Investigational Testing for Medical Devices. The Internal Working Group on Transplantation Outcomes was established to consider issues related to surveillance and adverse event reporting or organ, tissue transplantation and xenotransplantation. The Internal Working Group on Xenografts - Risks to Third Parties- was created to assess the issue of risk to third parties from proposed Clinical Trials using Xenografts. More information on the work of these committees will be discussed at the next EAC-XR meeting.

Action: The EAC-XR were asked to comment on the DRAFT Interim Guidance Document Clinical Trials Involving Xenografts. Comments should be forwarded to the EAC-XR Coordinator by September 10, 1999.

Dr. Marian Laderoute presented an overview of Xenotransplantation issues emphasizing how xenografts are different from biological drugs produced from animals and may present a different form of exposure between humans and animal materials. The transplantation of a Xenograft involves direct contact of viable cells producing viruses with human cells. Historically the exposures to animal materials generally did not involve immunosuppressed hosts. It remains to be determined to what level this difference will permit Xenozoonosis to occur and whether the risks are acceptable, for both the individual or the public at large.

Dr. Laderoute informed the EAC-XR that the intention to genetically modify pig donors so that their tissues and cells would not be easily rejected by human complement or by human anti-galacotose antibodies may impact our innate (naturally occurring) immunity. In this regard we have no experience and none of the studies to date have examined to what extent the infectious disease risks are increased when genetically modified animal tissues are grafted into primates. A number of key issues still need to be addressed, such as:

1. what non-human primates would be acceptable models for studying infectious disease risks,
2. should sexual transmittance studies be necessary,
3. what tests should be used for which known and unknown pathogens,
4. would it be useful to develop and validate surrogate markers for viral infections.

Dr. Laderoute also briefly summarized the key recommendations and issues discussed at the 1997 National Forum on Xenotransplantation.

Dr. Paul Sandstrom led the discussion on the recently published article in Science titled 'Search for Cross-species Transmission of Porcine Endogenous Retrovirus (PERV) in Patients Treated with Living Pig Tissue' which concluded the presentations. A study overview was given outlining the protocols used. Samples were collected up to twelve years post treatment for 160 patients who were treated with various living pig tissues. Investigations based on Polymerase Chain Reaction (PCR) and western blot analysis were performed. This included serum from 160 patients and peripheral blood mononuclear cells from 159 of the patients. No PERV infection was detected in any of the patients from whom sufficient DNA was extracted (97%) to allow complete PCR analysis. Persistent microchimerism (presence of donor cells in the recipient) was observed in 23 patients for up to 8.5 years.

The EAC-XR felt that further discussion was merited for the following areas:

• Informed consent linked to the Review Ethics Board function with respect to future clinical trials involving Xenografts,
• The Proposed Canadian Standard on Xenotransplantation, are they adequate, comments to the document should be forwarded to EAC-XR Coordinator,
• Risk to Third Party requires further review to identify comprehensive list of concerns.

Action: Comments on the Proposed Canadian Standard on Xenotransplantation should be discussed at the next EAC-XR meeting or forwarded to the Coordinator.

The committee felt more information would be useful regarding gene therapy and current retro viral research taking place in Canada. Speakers will be invited to the next EAC-XR meeting tentatively scheduled for November 2, 1999.

Meeting adjourned 3:30 pm

Secretariat: Ms. Sue-ann Blakely
September 7, 1999.