Consultation on the New Regulatory Framework for the Safety of Cells, Tissues and Organs (CTO)

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact: Policy and Promotion Division

Consultation on the New Regulatory Framework for the Safety of Cells, Tissues and Organs (CTO)

CTO consultation workshops were held in four locations across Canada (Toronto, Edmonton, Halifax and Montreal) in March 2005 to ensure that key stakeholders from all regions had access to a consultation in their area and had an opportunity to comment.

The objectives of the workshop were:

• to share information with stakeholders regarding the proposed CTO regulatory framework (Phase I);
• to obtain stakeholders' views and input on the proposed adverse event reporting system (Phase II); and
• to obtain stakeholders' views and input on the compliance monitoring and enforcement strategy options (Phase II).

Background documents provided to participants included the following:

1. Technical Requirements to Address the Safety of Cells, Tissues and Organs for Transplantation:
   1. Guidance Document: Basic Safety Requirements for Human Cells, Tissues and Organs for Transplantation and
   2. Directive: Technical Requirements to address the Safety of Cells, Tissues and Organs for Transplantation

After an initial welcoming address and introductory remarks from the Regional Director for the Health Products and Food Branch in the area, the following were presented over two days:

Day 1

• Welcome/Introductory Remarks
• 1. Health Canada's Policy Development Process
• 2. The New Regulatory Framework for CTOs-Developing a Common Understanding -Part 1
• 3. The New Regulatory Framework for CTOs-Developing a Common Understanding -Part 2
• 4a. Introduction to Adverse Reaction Reporting
• 4b. Introduction to Error and Accident Reporting
• 5. Adverse Reaction and E/A Reporting - Phase I
• 6. Proposed Options for Adverse Reaction and E/A Reporting in Phase II

Day 2

• 1. Introduction to Compliance Monitoring and Enforcement
• 2. Compliance Monitoring and Enforcement-Phase I
• 3. Proposed Options for Compliance Monitoring and Enforcement-Phase II
• 4. Next Steps

On each day of the consultation, participants participated in facilitated sessions in order to obtain their feedback regarding Phase II of the New Regulatory Framework for the Safety of CTOs for human transplantation. The questions in the workbooks below formed the basis for the facilitated session.

• 1. Participant Workbook- Cells, Tissues and Organs Regulatory Framework-Phase II Adverse Event Reporting (Day 1)
• 2. Participant Workbook- Cells, Tissues and Organs Regulatory Framework-Phase II Compliance and Enforcement Monitoring (Day 2)

Once we have received all comments from stakeholders, a final report will be placed at this location.

We encourage you to provide input prior to July 15, 2005 by completing the above-mentioned workbooks and returning them to:

Ms. Michèle Chadwick
Policy and Promotion Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Email: michele_chadwick@hc-sc.gc.ca
Phone: (613) 946-5730
Fax: (613) 952-5364

Establishments and individuals involved in the handling and /or processing of human cells, tissues and organs (CTO) for transplantation

Contact Policy and Promotion Division

Biologics and Genetic
Therapies Directorate
2nd Floor, Building #7
Address Locator # 0702E
Tunney's Pasture
OTTAWA, Ontario
K1A 0L2

July 29, 2005

05-116401-181

TO: Establishments and individuals involved in the handling and /or processing of human cells, tissues and organs (CTO) for transplantation

RE: Health Canada Directive to Address the Safety of HumanCells, Tissues and Organs for Transplantation

Please find enclosed the documents entitled, Technical Requirements to Address the Safety of Cells, Tissues and Organs for Transplantation (Directive) and Safety Requirements for Human Cells, Tissues and Organs for Transplantation (Guidance Document) dated July 2005. These documents are being re-issued by Health Canada to establishments and individuals in Canada involved in the handling and/or processing of human cells, tissues and organs (CTO) for transplantation. These documents replace the Directive and Guidance Document issued in January 2003. The changes in the Directive and Guidance Document are concurrent with the mandate of Health Canada; as such, amendments to the Directive and Guidance Document have been made with the health and safety of Canadians in mind. Electronic copies of these documents can be found on the Health Canada website at the following address: www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/cto_directive_e.html.

With respect to the changes within the Directive and Guidance Document, particularly noteworthy is the removal of the recognition of other standards as being equivalent to the requirements in the Directive and Guidance Document. The January 2003 version of the Guidance Document stated that other standards used in the community, such as the American Association of Tissue Banks (AATB), would be considered equivalent to the requirements of the Directive and Guidance Document. The 2005 Guidance Document no longer grants that equivalency to any other standard. The requirements in the Directive and Guidance Document must be met for all human cells, tissues and organs for transplantation that are processed, distributed and imported into Canada.

As with the original documents, the revised Directive and Guidance Document are based on National Standards for the Safety of Cells, Tissues and Organs for Transplantation and Assisted Reproduction, published by the Canadian Standards Association (CSA). As such, it is important that any issue regarding the applicability or the feasibility of the requirements therein be raised with the CSA. The Standards contain "Proposal for Change" forms. Please submit your comments to the CSA as per the instructions on the forms.

The July 2005 Guidance Document is an interim measure until the new regulations regarding the safety of human cells, tissues, and organs for transplantation come into effect. Health Canada strongly recommends that your establishment review this document carefully and make appropriate changes to its standard operating procedures, if required. It is in the best interest of the health and safety of Canadians for every establishment to comply with the Directive and Guidance Document. Should you have questions regarding the compliance of your establishment with these documents, please contact Health Canada for further guidance as to how to proceed in your particular circumstance.

If you have any questions concerning the Directive or Guidance Document, please do not hesitate to contact Liz Anne Gillham-Eisen of the Biologics and Genetic Therapies Directorate by e-mail at BGTD_PPD_DPP@hc-sc.gc.ca.

Yours sincerely,

Dr. Pierre J. Charest
A/Director General

Enclosure:

1) Technical Requirements to Address the Safety of Cells, Tissues and Organs for Transplantation (Directive).

2) Safety Requirements for Human Cells, Tissues and Organs for Transplantation (Guidance Document).

Technical Requirements to Address the Safety of Human Cells, Tissues and Organs for Transplantation (Directive)

This Directive replaces the Health Canada Directive issued in January 2003.

1. Purpose

The purpose of this Directive is to advise all establishments and individuals in Canada handling human cells, tissues and organs of the importance of adhering to standards of safety with respect to the processing, distribution and importation of these products for transplantation. This Directive applies to those establishments described below in "Scope".

2. Background

The therapeutic use of human cells, tissues and organs can enhance the quality and duration of life. Health Canada is the federal authority which regulates the safety, efficacy and quality of therapeutic products used in Canada, pursuant to the Food and Drugs Act. Health Canada works with provincial and territorial governments, other regulatory agencies, trade associations, health professionals and their associations and the Canadian public to fulfill its mandate.

Some cells and tissues are regulated under the Food and Drugs Act. For example, human semen used for assisted conception is regulated under its own set of regulations under the Food and Drugs Act, namely, the Processing and Distribution of Semen for Assisted Conception Regulations. Demineralized bone, heart valves and dura mater, are regulated as medical devices under the Medical Devices Regulations. Other human tissues, such as blood, are being regulated as drugs under the Food and Drug Regulations.

3. Current status

Health Canada is developing a new regulatory framework under the Food and Drugs Act for cells, tissues and organs which will be informed by the National Safety Standards that were developed and published by the Canadian Standards Association in summer 2003. Other key elements of the regulatory framework will include adverse event reporting and a compliance monitoring and enforcement strategy. The proposed regulatory framework will be aimed at maximizing the safety of human cells, tissues and organs available for therapeutic purposes.

Until the new regulatory framework is in place, Health Canada is recommending that establishments and individuals in Canada handling and/or processing human cells, tissues and organs adhere to the provisions of the Safety Requirements for Human Cells, Tissues and Organs for Transplantation (Guidance Document) herein with respect to the processing, distribution and importation of these products for transplantation. The attached Guidance Document sets out safety requirements with respect to donor suitability assessment and the collection/retrieval, processing, preservation, packaging, labelling, storage, quarantining, record keeping, distribution, importation, adverse event reporting, investigation and recall of cells, tissues and organs for transplantation.

Cells, tissues and organs that are not processed in accordance with the standards of safety specified in the attached Guidance Document raise a risk of being unsafe and of being manufactured, prepared, preserved, packaged or stored under unsanitary conditions; being adulterated or of having the potential to cause injury under normal conditions of use.

Consequently, in order to protect the health and safety of Canadians, where evidence shows that cells, tissues and organs are not processed in accordance with the Guidance Document, Health Canada will exercise its authority under Sections 8 and 19 of the Food and Drugs Act to prohibit the distribution of such products.

4. Scope

4.1

This Directive applies to human organs, and minimally manipulated human cells and tissue used in transplantation procedures. Minimal manipulation of cells and tissues is defined as:

1. in respect of a structural tissue, processing that does not alter the original characteristics that are relevant to its claimed utility for reconstruction, repair or replacement;
2. in respect of cells and nonstructural tissue, processing that does not alter the relevant biological characteristics of cells or tissues.

No person shall distribute, import or make available a cell, tissue or organ for transplantation unless the cell, tissue or organ has been processed or distributed in accordance with this Directive and the attached Guidance Document.

4.2

This Directive applies to establishments handling human cells, tissues or organs, which are involved in any of the following activities:

1. processing (as defined in the Guidance Document)
2. importation
3. distribution
4. transplantation

4.3

This Directive does not apply to :

1. cells, tissues and organs that are for autologous use;
2. cells, tissues and organs that are for non-homologous use;
3. cells, tissues and organs that are used in investigational testing involving human subjects under Part 3 of the Medical Devices Regulations or clinical trials under Division 5 of Part C of the Food and Drug Regulations;
4. Class IV medical devices that are regulated under the Medical Devices Regulations, for example heart valves, dura mater and demineralized bone;
5. whole blood, blood components and blood products, except for cord blood;
6. cells and tissues that are regulated under the Assisted Human Reproduction Act or any of its regulations; and
7. semen that is regulated under the Processing and Distribution of Semen for Assisted Conception Regulations.

5. Additional information

Additional Information on Health Canada's proposed new regulatory framework for cells, tissues and organs can be found at:

www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/cto_directive_e.html

Questions concerning this Directive should be referred to:

Liz Anne Gillham-Eisen
Policy and Promotion Division
Biologics & Genetic Therapies Directorate
Health Products and Food Branch
Health Canada
2nd Floor
Building 7, AL 0702A
Tunney's Pasture, Ottawa,
Ontario, K1A 0L2

E-mail: BGTD_PPD_DPP@hc-sc.gc.ca

Guidance Document: Basic Safety Requirements for Human Cells, Tissues and Organs for Transplantation

July 2005

© Her Majesty in Right of Canada
©Canadian Standards Association - 2003
Permission is granted to electronically copy and to print in hard copy for personal use only.

Table of Contents

• 1. Abbreviations And Explanatory Note
• 2. Definitions
• 3. Quality Management
  • 3.1 Quality Assurance
  • 3.2 Standard Operating Procedures
  • 3.3 Process Control
  • 3.4 Investigations
• 4. Record Keeping and Tracking
  • 4.1 Record Keeping Requirements
  • 4.2 Tracking (Traceability) Requirements
• 5. Donor Suitability Assessment
  • 5.1 General
  • 5.2 Suitability of Donors
  • 5.3 Documentation
  • 5.4 Medical History
  • 5.5 Donor Screening
  • 5.6 Testing
• 6. Retrieval, Processing, Preservation and Storage
  • 6.1 General
  • 6.2 Pooling
  • 6.3 Retrieval
  • 6.4 Processing and Preservation
  • 6.5 Packaging, Containers and Storage
  • 6.6 Labels, Inserts and Accompanying Documentation
• 7. Quarantine and Release
  • 7.1 General
  • 7.2 Exceptional Release
• 8. Distribution
  • 8.1 General
  • 8.2 Importer of Cells, Tissues and Organs
  • 8.3 Transportation
  • 8.4 Receiver of Cells, Tissues, and Organs
• 9. Adverse Event Monitoring and Recalls
  • 9.1 General
  • 9.2 Investigation, Notification, and Reporting
  • 9.3 Recall

1. Abbreviations And Explanatory Note

AIDS Acquired Immuno-Deficiency Syndrome
CJD Creutzfeldt-Jakob Disease
CMV Cytomegalovirus
EBV Epstein-Barr Virus
HBc Hepatitis B Core
HBsAg Hepatitis B Surface Antigen
HBV Hepatitis B Virus
HCV Hepatitis C Virus
HIV Human Immunodeficiency Virus
HLA Histocompatibility
HTLV Human T-cell Lymphotropic Virus
IgG Immune Globulin G
IgM Immune Globulin M
ODO Organ Donation Organization
SOPs Standard Operating Procedures

In this Guidance Document, "shall" is used to express a requirement, i.e., a provision that the user is obliged to satisfy; "should" is used to express a recommendation or that which is advised but not required; and "may" is used to express an option or that which is permissible within the limits of the Guidance Document. Notes accompanying clauses do not include requirements or alternative requirements; the purpose of a note accompanying a clause is to separate from the text explanatory or informative material.

2. Definitions

Accident--any occurrence, not associated with a deviation from standard operating procedures (SOPs), or applicable laws and regulations. An accident may occur during donor suitability assessment, retrieval, processing, preservation, packaging, labelling, storage, quarantine, evaluation, recordkeeping, adverse event reporting, distribution, importation or exportation, and recall of cells, tissues and organs. Such accidents may affect the performance, biocompatibility, or freedom from transmissible pathogens of the cells, tissues and organs or the ability to track cells, tissues and organs to the donor or recipient.

Adverse event--any unintended or untoward medical occurrence that may be consequent or related to cells, tissues or organs that are transplanted. An adverse event may be considered to be an incident or a reaction.

Container--a receptacle that is used to contain cells, tissues or organs and is in direct contact with the cells, tissues or organs.

Donor screening--the process for determining the suitability of a specific individual for cell, tissue, or organ donation based on medical, social, and sexual history, physical examination and autopsy finding (if an autopsy was performed).

Donor suitability assessment--the process for determining the suitability of a specific individual for cell, tissue or organ donation based on donor screening and donor testing.

Donor testing--the process for determining the suitability of a specific individual for cell, tissue or organ donation based on laboratory tests on a specimen collected from the donor to determine past or present infection with a relevant infectious disease or the presence of a genetic defect.

Error--a departure from the SOP or applicable laws and regulations during donor suitability assessment, retrieval, processing, preservation, packaging, labelling, storage, quarantine, evaluation, recordkeeping, adverse event reporting, distribution, importation or exportation, and recall of cells, tissues, or organs that may cause infectious disease transmission, adversely affect the clinical performance of cells, tissues, or organs, or interfere with the ability to track cells, tissues, or organs to the donor.

Exceptional release--the release of cells, tissues or organs to a transplant program from a donor in whom the donor suitability assessment has identified an increased risk for disease transmission.

Identification number--a unique numeric or alphanumeric designation assigned to, and thus associated with, a donor or recipient, a specific establishment and cells, tissues or organs, for the purpose of tracking and confidentiality. If donated cells, tissues and organs are divided, the unique donor identification number is distinctly associated with each part.

Importer--an establishment or individual that receives cells, tissues or organs from a foreign country.

Insert-- the material/paperwork accompanying the cells, tissue or organ that contains information about the graft, directions for use (including safe use), additives and warnings.

Label -- any legend, word, or mark attached to any cell, tissue, organ or package.
Note: Labels may include, for example, instructions for safe use, a list of additives, or warnings.

Organ Donation Organization (ODO) -- an organization or agency with the responsibility for the facilitation of cell, tissue or organ donation, retrieval and distribution that includes, but is not limited to, receiving referrals of cells, tissues or organs for donation; collecting the information necessary to determine the suitability of the donor and his or her cells, tissues or organs; offering the cells, tissues or organs to the appropriate transplant program; coordinating the retrieval of the cells, tissues or organs; preserving, storing, transporting, releasing and delivering the cells, tissues or organs to the transplant program; and documenting this process.

Note:

1. ODO services may include research activities.
2. Tissue donation organizations may fulfill the same responsibilities as an ODO.
3. The term "organ donation organization" is used in this Guidance Document in place of the term "organ procurement organization".

Package--any carton, receptacle or wrapper, including the label, container and contents of a container.

Processing--in respect of cells, tissues and organs, means any of the following activities:

1. donor screening;
2. donor testing;
3. donor suitability assessment;
4. retrieval;
5. post-retrieval testing;
6. preparation for use in transplantation;
7. preservation;
8. quarantine;
9. banking; and
10. labelling and packaging.

Quality assurance (QA)--part of coordinated activities to direct and control the activities of an establishment with regard to quality and to focus on providing confidence that quality requirements are being fulfilled.

Quarantine--the identification of cells, tissues and organs that are not suitable for use or that have not yet been characterized as being suitable for use. Includes storage in an area clearly identified for controlled sequestration and other procedures that prevent the release of such cells, tissues and organs.

Recipient--any individual who receives a cell, tissue or organ transplantation.

Serious adverse event--an adverse event in a recipient of a transplant that:

1. results in in-patient hospitalization;
2. results in prolongation of existing hospitalization;
3. results in persistent or significant incapability (including transmission of a disease or failure of the transplant's function or integrity);
4. is life threatening; or
5. results in death.

Source establishment--the ODO or the establishment involved in processing cells, tissues or organs from living or cadaveric individuals.

3. Quality Management

3.1 Quality Assurance

Each establishment shall establish, maintain and document quality assurance activities to ensure all policies, procedures, processes, products and services of the establishment conform to its Standard Operating Procedures (SOPs), this Guidance Document and applicable laws and regulations.

3.2 Standard Operating Procedures (SOPs)

3.2.1

Each establishment shall maintain SOPs. The SOPs shall include a detailed description of the following:

1. the procedures used for:
   1. donor suitability assessment;
   2. the retrieval, processing, preservation, packaging, labelling, storage, quarantine, evaluation distribution, importation or exportation and recall of cells, tissues and organs; and
   3. record keeping, adverse event reporting and notification.
2. the procedures used for establishment maintenance and cleaning and environmental monitoring;
3. the procedures used for equipment maintenance, cleaning, calibration and validation;
4. investigation of complaints;
5. copies of publications cited in support of the policies and procedures;
6. a description of the tests, procedures and tolerance limits applied; and
7. quality control activities.

3.2.2

Cells, tissues and organs shall be processed and preserved according to the SOPs.

3.3 Process Control

All processes shall be validated prior to implementation, revalidated whenever significant changes are made in the method or material being analyzed and when deviations from a validated process occur.

3.4 Investigations

Designated personnel shall investigate and document all errors, accidents, complaints, adverse events and recalls. The documentation shall include the nature of the event, the corrective actions recommended and implemented, the date and the personnel involved.

4. Record Keeping and Tracking

4.1 Record Keeping Requirements

4.1.1

Records shall be confidential, accurate, complete, legible and indelible.

4.1.2

The records shall provide a complete history of each donated cell, tissue or organ and shall cover all activities from informed consent and donor suitability assessment to the final disposition of the cells, tissues or organs.

4.1.3

All laboratory results and other tests used to determine the final release of cells, tissues or organs shall be maintained by the processor and distributor.

4.1.4

All manual transcription of test results shall be independently verified.

4.1.5

The donor record shall include:

1. the donor identification number;
2. documentation of each significant step in the donor suitability assessment;
3. documentation of donor testing for infectious disease;
4. documentation of notification, retrieval, labelling, processing, preservation, packaging, evaluation, storage, quarantine and distribution;
5. the identity of the person(s) performing the work and the dates of the various entries;
6. the test results and interpretation of the test results;
7. a complete history of the work performed to enable tracking of records to the particular cells, tissues and organs involved;
8. documentation of adverse events, problems, complaints, corrective actions, deviations from SOPs and product deficiencies;
9. the date and personnel involved in each phase of the process, i.e., from the time of donor screening and cell, tissue or organ retrieval to the final disposition of the cells, tissue or organ;
10. the donor log, where applicable; and
11. the destruction or other disposition of unsuitable or unused cells, tissues or organs.

4.2 Tracking (Traceability) Requirements

4.2.1

Each establishment involved in the retrieval, processing, distribution or storage of cells, tissues or organs shall have an identification number that allows for the tracking of cells, tissues or organs from the donor source to the recipient and vice versa and, if applicable, the tracking of archived serum samples and quality control specimens to the donor. All establishments handling the cells, tissues or organs shall ensure that their donor identification number matches the donor identification number of the establishment from which it acquired the cells, tissues or organs.

4.2.2

Each establishment involved in transferring or distributing cells, tissues or organs to other establishments shall have mechanisms in place to ensure communication between itself and those establishments for the purpose of tracking cell, tissue or organ donations from the donor to all consignees, as well as for the purposes of notification and recall. Consignees shall have mechanisms in place to permit the tracking of all recipients of cells, tissues and organs retrieved from a single donor.

4.2.3

Each establishment involved in the transplantation of cells, tissues and organs shall be able to identify the link to the recipient by a unique identification number (i.e., the recipient's transplant/medical/dental record shall include the donor identification number and the type of cell, tissue or organ transplanted).

4.2.4

Establishments shall keep accurate records of:

1. the distribution of all cells, tissues and organs, according to the donor identification number;
2. the type of cells, tissues or organs;
3. the donor identification number;
4. the personnel involved in procedures;
5. the identification of the recipient;
6. the dates of retrieval and transplantation;
7. the date of transplant and outcomes, where applicable.

5. Donor Suitability Assessment

5.1 General

Donor consent should be obtained according to applicable laws.

5.2 Suitability of Donors

5.2.1

The suitability of a specific individual for cell, tissue or organ donation shall be documented and shall be based on medical and social history, clinical status, physical examination, tests and autopsy (if performed).

5.2.2

A medical/sexual/psychosocial questionnaire shall be used for donor screening. The questionnaire shall include, but will not be limited to, questions to evaluate all of the general and specific contraindications/exclusion criteria set out in section 5.5.1 of this Guidance Document. The questionnaire shall be completed for each donor and will indicate the response for each question.

5.3 Documentation

Documentation of the donor suitability assessment shall include the following:

1. donor's name, address, identification number and date of birth;
2. date(s) of the interview;
3. completed donor consent form(s);
4. name of the healthcare professional who administered the questionnaire(s) and reviewed the medical records;
5. donor's medical records, if available;
6. date and results of physical examination;
7. completed medical, sexual, and social history questionnaire and date of completion;
8. dates and results of laboratory tests and, if applicable, the interpretation of the results;
9. hemodilution assessment, if required, accompanied by a statement indicating whether the donor received any transfusions or infusions prior to obtaining the blood sample for testing; and
10. donor log, if applicable.

5.4 Medical History

5.4.1 Perfusable Organ-Specific Requirements

5.4.1.1

For living and deceased donors, a donor history shall be obtained from all available medical sources, as well as the next of kin. This shall include the following:

1. any history of malignancy or tuberculosis or other communicable disease;
2. any history of other major illnesses, previous hospitalizations, previous surgical procedures, previous blood or blood-product transfusions, current medications and any drugs administered within the previous 48 hours;
3. any history of disease or abnormality of any of the consented organs or tissues;
4. previous residence or travel.

5.4.1.2

Additional requirements for cadaveric donors include:

1. the cause of death;
2. any episode affecting hemodynamic stability since the onset of critical illness, the treatment history and most recent status;
3. for a donor infant less than 18 months of age, a maternal history that includes:
   1. history of tuberculosis, hepatitis or other communicable disease;
   2. any high-risk behaviour for HIV [see section 5.5.1.1(g) for reference]; and
4. any history of sepsis since the onset of critical illness, its documentation (culture report) and treatment.

5.4.2 Lymphohematopoietic Cell-Specific Requirements

The donor's medical history shall include at least the following:

1. vaccination history;
2. travel history;
3. blood transfusion history;
4. pregnancy assessment for all female donors of childbearing potential; and
5. questions to identify persons at high risk for significant transmissible infections according to the authority having jurisdiction for donors of lymphohematopoietic cells.

5.5 Donor Screening

5.5.1 Contraindications or Exclusion Criteria

5.5.1.1 General

Examples of contraindications or exclusion criteria to donation of all cells, tissues and organs include, but are not limited to, the following:

1. death from an unknown cause;
2. death with neurological disease of an unestablished etiology (e.g., Alzheimer's, multiple sclerosis, Parkinson's, amyotrophic lateral sclerosis (ALS);
3. prion-related disease [e.g., Creutzfeldt-Jakob disease (CJD), family history of CJD, recipients of human-derived pituitary growth hormone or dura mater];
4. subacute sclerosing panencephalitis;
5. progressive multifocal leukoencephalopathy;
6. rabies;
7. high risk for human immunodeficiency virus (HIV);
   
   Note: The exclusionary criteria for HIV risk behaviours are outlined in the CAN/CSA-Z900.1-03, Cells, Tissues, and Organs for Transplantation and Assisted Reproduction: General Requirements, Annex E, "Exclusionary Criteria for Human Immunodeficiency Virus (HIV) Risk Behaviours".
8. persons with repeatedly reactive screening assays or who test positive for
   1. antibody to HIV types 1 or 2 (anti-HIV-1 or anti-HIV-2);
   2. hepatitis B surface antigen (HBsAg);
   3. antibody to hepatitis C virus (anti-HCV); or
   4. antibody to human T-cell lymphotropic virus types I or II (anti-HTLV-I or anti-HTLV-II);
9. active systemic bacterial, fungal or viral infection;
10. leukemias and lymphomas.

5.5.1.2 Tissue-Specific Requirements

In addition to the contraindications or exclusion criteria listed in section 5.5.1.1, exclusion criteria for tissue donors include, but are not limited to, the following:

1. active viral encephalitis or encephalitis of unknown origin;
2. malaria; and
3. tuberculosis.

5.5.1.3 Ocular Tissue-Specific Requirements

5.5.1.3.1

In addition to the contraindications or exclusion criteria listed in section 5.5.1.1, contraindications for tissues used for penetrating keratoplasty, lamellar or patch grafts, epikeratoplasty and for scleral tissues include, but are not limited to, the following:

1. congenital rubella;
2. Reye's syndrome;
3. active viral encephalitis or encephalitis of unknown origin or progressive encephalopathy;
4. active bacterial or fungal endocarditis;
5. active viral hepatitis;
6. intrinsic eye disease such as
   1. retinoblastoma;
   2. malignant tumours of the anterior ocular segment, of primary or metastatic origin (e.g., adenocarcinoma);
   3. active ocular or intraocular inflammation;
   4. congenital or acquired disorders of the eye that would preclude a successful outcome for the intended use; or
   5. pterygia or other superficial disorders of the conjunctiva or corneal surface involving the central optical area of the corneal button;
7. active disseminated lymphomas; and
8. prior intraocular or anterior segment surgery such as,
   1. refractive corneal procedures; and
   2. laser photoablation surgery.

Note: Corneas from patients with anterior segment surgery may be used if they are screened by specular microscopy and meet the eye bank's endothelial cell count standards as outlined in the SOPs. Retinal and panretinal photocoagulation may be considered following clearance from the Medical Director

5.5.1.3.2

Notwithstanding the contraindications specified in section 5.5.1.3.1 (f) and (h), tissues may be transplanted if deemed acceptable for a specific use by the Medical Director.

5.5.2 Physical Examination

A physical examination of the donor must be performed by a qualified person to assess any evidence of high-risk behaviour, signs of malignancy, bacterial or viral infection and trauma to the retrieval site.

5.6 Testing

5.6.1 General

5.6.1.1

The SOPs shall describe the tests and procedures required for measuring, assaying or monitoring properties of cells, tissues and organs essential to the evaluation of their safety for transplantation.

5.6.1.2

Testing shall be performed by a laboratory that meets applicable laws and regulations, or in the case of imported cells, tissues and organs, by a laboratory that meets current requirements of the donor centre of origin.

5.6.1.3

Testing of donor blood for specified infectious agents shall be performed with in vitro diagnostic devices that comply with federal regulatory requirements. The manufacturer's instructions for the performance and interpretation of its test shall be followed. Blood donor screening tests should be used. Where Nucleic Acid Tests (NAT) are available for blood donor screening, they should be used in addition to the required serological tests.

5.6.1.4

For the testing of donors where only cadaveric blood is available, establishments should use a test that is specifically licensed or authorized for the testing of cadaveric blood.

5.6.1.5

Where test kits that comply with federal regulatory requirements are not available for a test specified in this Guidance Document, the laboratory specified in section 5.6.1.2 should ensure that all tests used for the evaluation of the safety of cells, tissues and organs are validated to support the use of the method for the intended applications.

5.6.1.6

Test results shall be documented in the donor record.

5.6.2 Procedures for Serological Screening Tests for Infectious Diseases

5.6.2.1 General

Serological tests for infectious diseases specified in 5.6.4 shall be performed and interpreted according to manufacturer specifications.

5.6.2.1.1

Cells, tissues or organs may be released for transplantation if the donor's blood sample is reactive for a nontreponemal screening test for syphilis but negative for a treponemal-specific confirmatory test.

5.6.2.2 Tissue-Specific Requirements

Results of the infectious disease tests specified in section 5.6.4 are acceptable if performed on a blood specimen taken within 7 days prior to donation for deceased donors and within 30 days of donation for living donors.

5.6.2.3 Perfusable Organ-Specific Requirements

For living donors, the infectious disease tests specified in section 5.6.4 shall be performed on a blood specimen taken within one month prior to the surgery. The minimum testing required at the transplant centre for the anesthetic and operative procedure shall be performed.

Note: It is recommended that living donors be retested at the time of donation, even if the results are not available before the time of transplantation.

5.6.2.4 Lymphohematopoietic Cell-Specific Requirements

The infectious disease tests specified in section 5.6.4 shall be performed within 30 days prior to collection (unless a previously positive test has been documented). In the event that collections from the same donor are performed more than 30 days apart, donors shall be retested for the infectious disease agent and markers.

5.6.2.5 Archived Cell, Tissue, Organ or Serum Samples

It is recommended that cell, tissue or blood samples be collected from the donor for future testing, where related to the safety of transplantation (e.g., for future testing when new serological tests for existing or new pathogens are adopted for donor screening). Cell, tissue, organ or serum samples shall be stored frozen.

5.6.3 Minimum Serological Testing for Infectious Diseases

5.6.3.1 General

Minimum donor serological testing shall include the following:

1. anti-HIV-1, and anti-HIV-2;
2. HBsAg;
3. anti-HCV.

5.6.3.2 Tissue-Specific Requirements

In addition to 5.6.4.1 donors shall be tested for:

1. anti-HTLV-I and anti-HTLV-II;
2. syphilis.

Note: It is recommended that donors of tissues subject to the living donor quarantine requirements also be tested for total antibody to hepatitis B core (total anti-HBc, i.e., IgM and IgG) to prevent the processing and storage of tissues from donors who are positive for these markers.

5.6.3.3 Perfusable Organ-Specific Requirements

In addition to the tests specified in section 5.6.4.1,

1. donors shall be tested for:
   1. total anti-HBc, and
   2. toxoplasmosis for heart donors, which may be done retrospectively. The presence of toxoplasmosis and the risk of transmission of this disease shall be screened by testing for the presence of toxoplasmosis antibody in the donor's serum using a medically acceptable test (e.g., enzyme-linked immunoassay test); and
   3. syphilis (note: syphilis testing for organ donors is only mandatory if the organs are not stored in a culture media at 4 C or below for more than 24 h).
2. it is recommended that donors also be tested for:
   1. antibody to cytomegalovirus (anti-CMV IgG and anti-CMV IgM);
   2. Epstein-Barr virus (antibody to EBV, anti-EBV nuclear antigen (anti-EBNA) IgG, or anti-viral capsid antigen (anti-VCA) IgG), particularly for negative potential recipients.

5.6.3.4 Lymphohematopoietic Cell-Specific Requirements

In addition to the tests specified in section 5.6.3.1 donors shall be tested for:

1. anti-HTLV-I and anti-HTLV-II;
2. syphilis;
3. anti-CMV.

5.6.3.5 Living Donor Tissue Quarantine

Allograft tissues from living donors that are going to be stored shall be held in quarantine for at least 180 days, at which time the donor shall be retested for:

1. anti-HIV-1 and anti-HIV-2;
2. anti-HBc (IgG or total);
3. anti-HCV.

Note: Postquarantine testing before release of tissues from infant donors may require surrogate testing, as described in Clause 5.6.3.6.

5.6.3.6 Fetal or Infant Donors

To address possible vertical transmission of infectious agents in donors under 18 months of age, or up to 12 months beyond breast-feeding, the birth mother shall also be tested for total anti-HBc, in addition to tests specified in section 5.6.3 as applicable.

5.6.4 Transfusions and Hemodilution

5.6.4.1

Testing shall be performed on a pre-transfusion/infusion blood sample taken as near to the time of retrieval as possible. If no such sample is available, benchmarks for hemodilution shall be applied.

5.6.4.2

It is recommended that testing be done on the most recent pretransfusion/infusion specimen for which identity and quality can be ensured.

5.6.5 Bacteriological Testing

5.6.5.1 Tissue-Specific Requirements

Bacteriological testing of tissues intended for transplantation shall be performed as follows:

1. Representative bacteriological cultures from each excised tissue (e.g., swab culture or tissue biopsies) shall be obtained aseptically into appropriate culture media or transport medium at the time of retrieval. These cultures shall be taken before the tissue is exposed to any antibiotic-containing preparations.
2. Representative tissue shall be cultured after secondary sterilization procedures according to the SOP for each tissue.
3. Cultures shall be performed for both aerobic and anaerobic organisms, according to approved protocols, so that both rapid- and slow-growing organisms will be detected.
4. Tissues showing bacterial contamination at the time of retrieval may be transplanted if a suitable protocol for disinfection is in place. Organisms shall be identified to the genus level, and the tissue shall be disinfected, either while in process or in a terminal sterilization event, before transplantation is done.
5. If gram negative pathogens are cultured, the tissue shall not be released for transplantation unless it is effectively secondarily sterilized according to validated protocols.
6. When culture results of certain tissues are not available by the time of transplantation (e.g., fresh osteochondral allografts that, because of tissue viability issues, must be transplanted promptly), the results shall be forwarded to the end-user physician as soon as they become available.
7. Each processing step in which tissue is unwrapped and rewrapped shall require repeat bacteriological cultures to rule out contamination during the procedure.
8. Tissue shall be discarded if the final culture results are positive.

5.6.6 Other Tests

5.6.6.1 Blood Typing

Donor blood type (A, B, AB, O), Rh factor and histocompatibility (HLA) typing shall be required, where clinically indicated, for donation of applicable cells, tissues and organs. The tests for donors of lymphohematopoietic cells shall also include HLA-A, B, DR typing and appropriate red cell compatibility with the recipient.

5.6.6.2 Perfusable Organ-Specific Requirements

5.6.6.2.1

General tests shall determine the following:

1. height;
2. weight;
3. ABO blood type;
4. complete blood count (CBC);
5. levels of serum electrolytes;
6. levels of creatinine; and
7. chest X-ray.

5.6.6.2.2

At a minimum, the following tests shall be performed for potential specific organ donors:

1. Kidney: serum electrolyte testing, urea testing, urinalysis and creatinine;
2. Heart: chest X-ray; electrocardiogram (ECG) and 2D echocardiography;
3. Lungs: chest X-ray, pO2 on 100% oxygen after being on partial end-expiry pressure (PEEP) at 5 cm H2O for 15 min and tracheal aspirate for gramstain.
4. Liver: bilirubin testing, either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and either prothrombin time (PT) or International Normalized Ratio (INR).
5. Pancreas: blood sugar and amylase.

5.6.6.3 Ocular Tissue-Specific Requirements

5.6.6.3.1 Gross Examination

The corneal-scleral rim shall be initially examined grossly for clarity, epithelial defects, foreign objects, contaminations and scleral colour, e.g., jaundice.

5.6.6.3.2 Slit-Lamp Examination

The cornea shall be examined for epithelial and stromal pathology and in particular, endothelial disease. Enucleated whole globes shall be examined in the laboratory prior to distribution and/or corneal excision. If in situ corneal excision is performed, examination of the donor eye anterior segment with a penlight or portable slit-lamp shall be required. After corneal excision, the corneal-scleral rim shall be evaluated by slit-lamp biomicroscopy, even if the donor eye has been examined with the slit-lamp prior to excision of the corneal-scleral rim, to ensure that damage to the corneal endothelium or surgical detachment of Descemet's membrane did not occur.

5.6.7 Notification

5.6.7.1

Positive or reactive transmissable disease test results, either confirmed or discordant, obtained from either a living or deceased donor shall be reported to the appropriate health authorities in accordance with federal, provincial and territorial requirements. Positive, reactive or discordant test results shall be immediately reported to all organ donation organizations, tissue and cell banks and transplant programs in receipt of cells, tissues or organs from the donor.

5.6.7.2

Living donors shall be notified of all confirmed positive results.

5.6.7.3

For deceased donors, the donor program shall inform the donor's physician of record prior to death, or the physician who signed the death certificate, of confirmed positive test results.

6. Retrieval, Processing, Preservation and Storage

6.1 General

6.1.1

All nondisposable surgical instruments, devices and supplies used for retrieval, processing and preservation shall be cleaned, disinfected and/or sterilized between donations, as described in the SOP, to prevent contamination and cross-contamination.

6.1.2

Protocols shall be developed, implemented and documented for the validation or qualification of significant products of facilities, processes, equipment, reagents, labels, containers, packaging materials and computer systems.

6.1.3

The establishment shall validate and document methods, time limits, and environmental conditions to maintain the integrity of cells, tissues and organs and to prevent contamination. These shall include time limits, environmental conditions and acceptable temperature ranges for retrieval, processing, preservation, storage and transportation (if applicable).

6.1.4

The SOPs shall describe:

1. the storage temperatures and environmental conditions for all cells, tissues and organs and the procedures to follow in case of power failure or other errors or accidents during storage;
2. procedures to follow when cells, tissues or organs are exposed to environments outside of recommended storage limits; and
3. methods to prevent cross-contamination between cells, tissues and organs.

6.1.5

Reagents used in the collection, processing, preservation and storage shall be of appropriate grade for the intended use and shall be sterile. If commercially prepared devices or reagents are not available and in-house devices or reagents are used, the procedures for their production shall be validated.

6.1.6

The concentration of the reagents used (e.g., cryoprotectant, isotonic solutions, antibiotics, disinfectants) and the acceptable residual amount of reagent shall be documented in the SOP manual.

6.2 Pooling

6.2.1

Pooling of cells and tissues from multiple donors is allowed only in cases where it is required to obtain a therapeutic dose for a single recipient. Pooling of cells and tissues shall be documented in the SOP.

6.2.2

Lymphohematopoietic cells may be pooled from different sources from the same donor (e.g., marrow and peripheral blood). Pooling of lymphohematopoietic cells shall be documented in the SOP.

6.3 Retrieval

6.3.1

Time constraints for postmortem retrieval and the appropriate temperature for holding a donor until retrieval shall be determined and documented in the SOP of the retrieving establishment.

6.3.2

Cells, tissues and organs shall be retrieved using aseptic techniques and preserved within time intervals for the retention of biologic functions, in a way that is compatible with the intended use of the cells, tissues and organs.

6.3.3

Each donation shall be documented and a record retained by the donor retrieval establishment. The records shall include the following:

1. the name, address and identification number of the retrieving establishment;
2. documentation of informed consent;
3. the donor's name, age, sex and identification number;
4. the type of reagents, lot number, expiration date and manufacturer of the reagents and supplies used;
5. a description of and identification number for all cells, tissues or organs retrieved;
6. the date and time of retrieval;
7. the names of staff involved in retrieving the cells, tissues or organs; and
8. the disposition and recipient identification number of all cells, tissues or organs retrieved.

6.4 Processing and Preservation

Records of processing and preservation shall include the following:

1. the donor identification number, time and date of receipt of cells, tissues or organs from the retrieval establishment and documentation of the storage conditions, if applicable;
2. the cell, tissue or organ identification number and type of cells, tissue or organ being preserved;
3. the date, time of processing and preservation;
4. the names of the personnel involved in the procedures;
5. the cell, tissue or organ measurements;
6. any observed defects in the cells, tissues or organs;
7. the expiration date and time;
8. a description of any cells, tissues or organs sampled for testing/validation;
9. the results of microbiological tests (e.g., cultures);
10. the establishment identification number;
11. the recipient identification numbers;
12. the disposition of all cells, tissues or organs processed or preserved;
13. the type, lot number, manufacturer and expiration date of supplies and reagents used to process and/or preserve the cells, tissues or organs;
14. the residual amounts of additive (e.g., antibiotics), if applicable; and
15. the residual moisture content, if applicable.

6.5 Packaging, Containers and Storage

6.5.1

All materials that come into contact with the cells, tissues or organs shall be sterile. The establishment shall determine that containers and packaging materials used in the retrieval, processing, preservation and storage of cells, tissues and organs are for the intended purpose, as defined in the SOPs.

6.5.2

Containers and packaging materials shall maintain the integrity, quality, function and sterility of cells, tissues and organs for the entire shelf life, and shall not produce toxic residues during storage. Methods and materials to prevent or indicate the occurrence of tampering should be applied.

6.6 Labels, Inserts and Accompanying Documentation

6.6.1 General

Cells, tissues and organs shall be labelled for identification and tracking during all phases of retrieval, processing, preservation, storage and distribution. The donor identification number (see Clause 4.2.1) shall be included on the identification label of the cells, tissues or organs to facilitate donor/recipient tracking.

6.6.2 Information Requirements

The label and/or insert should identify if appropriate and applicable:

1. the name and identification number of the cells, tissues or organs;
2. the name and address of the establishment of origin of the cell, tissue or organ donation;
3. the donor identification number;
4. date of collection/retrieval;
5. the date of screening and testing of the donor;
6. the specimens tested;
7. the serological and microbiological tests performed and, if necessary, the interpretation of the test results; and
8. any special instructions for storage and handling.

6.6.3 Additional Requirements

In addition to the information requirements specified in section 6.6.2, the label and/or insert should include the following if appropriate and applicable:

1. the name and address of the importer and tissue distribution intermediaries;
2. date and time of death;
3. the volume, size, number of cells and a description;
4. date of cryopreservation or date and time of preservation;
5. the cryoprotectant used and concentration;
6. the type and amount of antibiotic used;
7. the presence of known sensitizing agents;
8. the results of tissue analysis;
9. blood types and Rh factor;
10. the expiry date;
11. the sterilization procedure used;
12. the preservative used and their concentration;
13. the amount, size, dimensions, weight and/or anatomical details of the tissue;
14. name and quantity of perfusion solution used;
15. date and time of aortic clamping for organ donations;
16. instructions for maintaining recipient tracking;
17. instructions for adverse event reporting;
18. biohazard label, if applicable; and
19. recommended storage temperature.

6.6.4 Containers

Containers shall be labelled so as to identify the cell, tissue or organ name and the cell, tissue or organ identification number.

6.6.5 Imported Cells, Tissues and Organs

For imported cells, tissues or organs, the outer shipping container shall display clearly, on the outside surface of that container:

1. the name and business address of the establishment of origin of the cell, tissue or organ donation;
2. type of cell, tissue or organ;
3. name, address and telephone number of the Canadian importer;
4. recommended storage conditions; and
5. a declaration signed by the foreign establishment of origin, or its authorized agent, certifying that the cell, tissue or organ has been processed in accordance with the requirements specified in this Guidance Document.

7. Quarantine and Release

7.1 General

Cells, tissues and organs shall be quarantined until:

1. donor suitability assessment has been completed (see Sections 5.1 to 5.5);
2. infectious disease testing has been completed and found to be negative (see Section 5.6);
3. compliance with quality control tests and procedures has been demonstrated; and
4. investigation of errors or accidents has been completed.

7.2 Exceptional Release

7.2.1

A source establishment may offer cells, tissues and organs for exceptional release that have not been processed in accordance with this Guidance Document if the following conditions are met:

1. the transplant physician or dentist justifies the request based on their clinical judgment, and requests their medical director to authorize the exceptional release;
2. the medical director of the transplant establishment authorizes the exceptional release; and
3. the transplant establishment obtains the informed consent of the recipient.

7.2.2

A source establishment that distributes cells, tissues or organs under section 7.2.1 shall put a notice of exceptional release in its record.

7.2.3

A transplant establishment that authorizes the exceptional release of cells, tissues or organs under 7.2.1 shall put a notice of exceptional release in its record and send a copy of the notice to the source establishment.

7.2.4

A notice of exceptional release shall contain all of the following information:

1. the provisions of this Guidance Document with which the cell, tissue or organ is not in compliance at the time of its release;
2. the justification for the release that formed the basis for the medical director's decision to authorize it;
3. the name of the source establishment that distributed the cell, tissue or organ;
4. the name of the transplant establishment, of the transplant physician or dentist and of the medical director who authorized the release; and
5. the time and date of the release and a copy of the written authorization signed by the medical director.

7.2.5

A source establishment that releases a cell, tissue or organ under 7.2.1 before the donor suitability assessment is complete shall, after the release, complete the assessment and carry out any other appropriate follow-up testing and forward the results to the transplant establishment.

8. Distribution

8.1 General

8.1.1

Each establishment that distributes cells, tissues or organs to another establishment shall provide the receiving establishment with the appropriate labelling and/or package inserts. Copies of any other information that is required to assess the suitability of the donor or the cells, tissues or organs for transplantation, except information that compromises donor confidentiality, shall be provided to the transplanting physician on request.

8.1.2

The records maintained by the distributing establishment shall include the donor identification number for cells, tissues or organs. In addition, the records should include, but not be limited to, the following:

1. the name and address of the receiving establishment;
2. the name of the establishment personnel who placed the request;
3. the name of the establishment personnel filling the request;
4. the date the request was placed and filled;
5. the type and quantity of cells, tissues or organs requested;
6. the retrieval and/or expiration dates;
7. the type and amount of refrigerant used for shipment, if applicable;
8. the date of shipment; and
9. recipient identifying information.

8.2 Importer of Cells, Tissues and Organs

8.2.1

The importer shall verify that the foreign processor of the cells, tissue or organ is in compliance with the requirements of this Guidance Document and applicable laws and regulations.

8.3 Transportation

8.3.1

Transportation arrangements by all establishments shipping cells, tissues or organs shall not risk the safety and integrity of the cells, tissues or organs. The shipping container shall be validated to ensure that the safety and integrity of cells, tissues and organs is maintained during transit.

8.3.2

The exterior of the shipping container should clearly display, if applicable and appropriate:

1. the name, address, donor identification number, and telephone number of the distributing and receiving establishments;
2. the type of cells, tissues, or organs;
3. the type and quantity of the refrigerant used;
4. any enclosed hazardous material;
5. recommended storage conditions; and
6. any special handling instructions.

8.4 Receiver of Cells, Tissues, and Organs

8.4.1

All establishments receiving cells, tissues and organs shall be responsible for verification of shipment and for obtaining and retaining records that allow tracking of donor cells, tissues and organs to the recipient. The transplant centre shall retain all recipient information and ensure that its records link the donor to the recipient.

8.4.2

Agreements shall be in place between all cell, tissue or organ processors and distributors and the last establishment that receives the cells, tissues or organs to allow access to all information required for donor-recipient tracking (see Clause 4). These agreements shall be documented in the SOP of the processor, distributor and last establishment to receive cells, tissues or organs.

8.4.3

The receivers of cells, tissues or organs shall promptly provide information to the processors and distributors of cells, tissues or organs about complications or technical problems with the use of the cells, tissues or organs.

8.4.4

All cells, tissues and organs forwarded to another establishment by the receiver shall be accompanied by the appropriate labelling and/or package insert to facilitate tracking and suitability.

9. Adverse Event Monitoring and Recalls

9.1 General

All confirmed positive tests for transmissible diseases in the recipient, suspected of being attributable to cell, tissue or organ transplantation shall be reported in a timely fashion to establishments and to physicians involved in any manner with the cells, tissues or organs retrieved from the same donor and to public authorities as required by applicable laws and regulations. If the event is reported verbally, a confirmatory written notice must be sent as soon as possible. Notification shall be documented in the donor's records.

9.2 Investigation, Notification, and Reporting

9.2.1

Identified transmission of disease and/or suspected serious adverse events shall be reported to federal, provincial, territorial or local health authorities as required by law.

9.2.2

Where there is evidence or reasonable grounds to believe that a transmissible agent or disease has been transmitted through the transplant, the establishment shall, without delay:

1. stop the distribution of all cells, tissues and organs in his or her possession having the same donor identification number as the cells, tissues and organs suspected of infectious transmission; and
2. provide a written report to the source establishment;
   1. advising that the cells, tissues or organs that the source establishment processed may be contaminated by a named confirmed or suspected infectious agent; and
   2. specifying the donor identification number of the suspected cells, tissues and organs.

9.2.3

Where a source establishment receives a report as described in Clause 9.2.2, or otherwise has reasonable grounds to believe that cells, tissues or organs already distributed may be contaminated by an infectious or transmissible agent or integrity may be compromised, the establishment shall, without delay:

1. identify the donor of the cells, tissues or organs and quarantine all cells, tissues or organs from the donor that are in the establishment's possession;
2. use all reasonable means to identify and locate each establishment that received cells, tissues or organs obtained from the donor;
3. give a written notice specifying the donor identification number of the cells, tissues or organs believed to be contaminated, naming the confirmed or suspected infectious or transmissible agent or the compromise of integrity, and indicating that the cells, tissues or organs shall be quarantined pending the completion of an investigation or must be destroyed. This notice shall be given to
   1. any person to whom the establishment distributed cells, tissues or organs having the donor identification number specified in the notice; and
   2. any other person who the establishment identified as receiving cells, tissues or organs from that donor source; and
   3. conduct an investigation to determine whether any of the cells, tissues or organs from the donor source are contaminated by an infectious or transmissible agent or compromise of integrity.

9.2.4

Every establishment shall, at the request of the source establishment conducting the investigation, provide the source establishment with any relevant information in its possession with respect to cells, tissues or organs that were distributed.

9.2.5

Where the results of the investigation demonstrate that the cells, tissues or organs are not contaminated by an infectious agent, the source establishment shall notify each person contacted about the potential infectious agent, in writing, that it is permissible to distribute the cells, tissues and organs having the donor identification number specified in the list of cells, tissues or organs that are not contaminated.

9.2.6

Where the results of the investigation demonstrate that all or some of the cells, tissues or organs are contaminated by an infectious agent, or the results are inconclusive as to whether the cells, tissues or organs are contaminated, the source establishment shall notify each person contacted about the potential infectious agent, in writing, that the cells, tissues or organs having the donor identification number specified in the list of cells, tissues or organs that are contaminated must be collected by the source establishment or destroyed.

9.2.7

Where an establishment receives a notice from the source establishment about a potential infectious agent, the establishment shall provide a written report to the source establishment, as soon as possible, indicating for each donor identification number referred to in the notice the number of cells, tissues or organs received by the establishment and the number that was distributed or destroyed.

9.3 Recall

The SOP shall describe the procedure for recall or notification, as well as all documentation required. Documentation shall include the following:

1. reason for the recall;
2. steps taken to quarantine recalled cells, tissues or organs that have not been transplanted or the return of such cells, tissues or organs to the establishment;
3. all communications and correspondence regarding the recall;
4. final disposition of cells, tissues or organs;
5. corrective actions recommended and implemented;
6. notification of recipients; and
7. packaging and shipping instructions for consignees, if applicable.

Opening Remarks Consultation on the Proposed New Regulatory Framework for the Safety of CTO for Transplantation

Contact: Policy and Promotion Division

• Good morning ladies and gentlemen. It is my pleasure to welcome you to this consultation on the proposed new regulatory framework for the safety of cells, tissues and organs for transplantation.
• Thank you for taking time out of your busy schedules to let us inform you on what the new regulations might require, and to provide input into the proposed compliance monitoring and enforcement and adverse event reporting before decisions are made.
• This consultation is part of Health Canada's commitment to working with stakeholders to ensure a high standard of safety, quality and efficacy in all the products we regulate.
• The reality for today's regulator can be characterized by the trinity of rapid technological advancement, complex policy issues, and increased public demands for greater openness, transparency and flexibility from their government.
• The challenge for the regulator is to realize the tremendous benefits that closer alignment and cooperation - brought about in part through consultations such as this one - can offer in addressing today's reality while ensuring that any approach respects our unique mandate and obligations toward the broader public interest.
• At the end of the day Health Canada's job, and the job of every regulator, is to remain firmly focussed on one priority - the best interests of the public we serve.
• This understanding is consistent with Health Canada's pursuit of a regulatory platform the for 21st Century - one that is flexible, risk based, and supportive of innovation, while fully minimizing health risks.
• The development of any new regulatory framework must provide an active role for governments, industry and citizens in making the system more effective. It is through this active role, along with openness and transparency, that relationships of trust will flourish.
• Stakeholder consultation is part of that active role, and a very important aspect of the regulatory work undertaken at Health Canada. Only through the eyes of our stakeholders can we really understand what the impacts of our activities will be, or whether we have, in fact, turned over every stone and considered every possibility.
• The new CTO regulations will make reference to standards developed by Canadian experts in the field of transplantation. This approach is regarded internationally as a cutting edge model that we believe will allow us to better serve the interests of Canadians and keep pace with a rapidly evolving health care sector.
• On the strength of this approach, Health Canada was recently invited to collaborate with the World Health Organization to identify essential requirements for the safety, quality and efficacy of cells and tissues for transplantation and to collaborate with other countries in the development of international specifications for submission to the WHO Expert Committee on Biological Standardization.
• We see the benefits of our new CTO regulatory framework as being added protection for the people of Canada, heightened ability to anticipate and manage health risks, harmonization with the international community and ease of administration for medical and industry establishments.
• The task before us over the next two days is a challenging one. While you will learn more about the proposed new regulatory framework, we will learn more about and how the proposed options fit with your practices and expectations.
• Critical success factors over the next two days include good communication and common understanding. I believe we have the basis for these elements, and wish you a productive meeting.

Overview of Policy and Regulatory Development: Presentation 1 - Consultation on the New Regulatory Framework for the Safety of Cells, Tissues and Organs (CTO), March 2005

Contact: Policy and Promotion Division

Policy Development: The Decision-Making Framework

Policy Development Process

• Step 1: Identifying Issue and its Context
  • the nature of the issue, its relevance to the directorate mandate and its level of priority.
• Step 2: Assess Risks and Benefits
  • collecting and interpreting data to identify potential cause(s)
  • understanding social, cultural, political, economic, international and legal implications of the issue as well as public view of acceptable risk
• Step 3: Identify and Analyze Options
  • once options are identified, must determine their effectiveness in achieving the desired outcome
  • tools include: cost-benefit, consultations, evaluation
• Step 4: Select a Strategy
  • provide clear advice on a series of policy options
  • options include (but are not limited to):
    • revocation, amendment or development of a regulation
    • development of a guidance document
    • issue closure with no action required
• Step 5: Implement the Strategy
  • the recommended strategy selected is to be implemented
• Step 6: Evaluate the Solution
  • assesses the effectiveness of the strategy selected and provides policy developers with lessons learned and recommendations for improvement
  • Involve interested and Affected Parties

Legislation

• An Act provides a legal framework that embodies the underlying principles of a program and the fundamental policies that are unlikely to change.
• Steps in the legislative process:
  • Memo to Cabinet seeking approval
  • sponsoring Minister presents Bill
  • 3 readings in the House of Commons and Senate
• Suitable when:
  • no other Act addresses a new or emerging issue;
  • the current Act does not provide sufficient regulatory authority to expand on existing regulations;
  • court decisions may result in the need for the revision of an Act or its provisions.

Regulation

• Are expressions of policy having the force of law that are issued by an executive authority of government
• In many situations, a hybrid approach between legislative and non-legislative instruments will be considered
• Suitable when:
  • non-legislative (voluntary) alternatives will not stand alone
  • compliance with desired behaviour must be compelled

Policy/Guidance

• Outlines how government will meet a legal obligation
• Interprets a regulation
• No legal force
• Can NOT contradict or override a regulation
• Policies and/or guidance can be amended or modified, as needs require, without any legal formalities being met
• Suitable when:
  • compliance with desired behaviour is expected to be high
  • issue is not a significant threat to core values

Conclusion

The preferred instrument will result from a strategy to address an issue following a comprehensive analysis based on dialogue within the Directorate, the Branch, the Department, and various stakeholders.

Objectives for this CTO Consultation

• to share information with stakeholders regarding the proposed CTO regulatory framework (Phase I);
• to obtain stakeholders' views and input on the proposed adverse event reporting system (Phase II); and
• to obtain stakeholders' views and input on the compliance monitoring and enforcement strategy options (Phase II).

New CTO Regulatory Framework Developing a Common Understanding (Part 1) Presentation 2

Contact: Policy and Promotion Division

Health Products and Food Branch Mandate

• To take an integrated approach to the management of risks and benefits to health, related to health products and food by:
  • minimizing risk factors to Canadians while maximizing safety provided by the regulatory system
  • authority - Food and Drug Act and Regulations

Health Canada Principles

• Safety and prevention is key
• Nationally integrated
• Transparent approach
• Clear accountability
• Harmonize internationally when possible, but identify areas where we can lead

Health Canada Regulations Considerations

• F/P/T Responsibility
  • 10 provinces and 3 territories, each with responsibility over of management and delivery of healthcare within
• Legal Authority
  • Food and Drug Act - Safety of the CTO
• Cost-Benefit
• International
  • bordered by US, with exchange of CTO across border in each direction

The Division of Responsibilities

Federal

Leadership
Regulation under Food and Drugs Act
National Disease Surveillance (PHAC)

Provincial / Territorial

Health Professionals
Transplant Programs
Hospitals & Health Authorities
Public Health

Source Establishments

Tissue Banks
Organ Donation Organizations
Live Donor Transplant Programs
Stem Cell Programs

Other Players

Donors & Recipients,
NGOs
Distributors and Importers

Complexity of Process

CTO Regulatory Framework Current Situation

• Myth:
  • Health Canada is developing regulations for CTO because there currently are none
• Truth:
  • food, drugs, medical devices and other therapeutic products are regulated under the provisions of the Food and Drug Act and Regulations
• However:
  • there are gaps in the current regulations
    • specific regulations for some tissue types but not others
    • archaic product definitions which present challenges to the regulation of CTO
      • Drug
      • Medical Device

CTO Regulatory Framework Solution

• Revise the current CTO Regulatory Framework
• Need a modern, responsive and comprehensive approach
• Health Canada will implement a new regulatory framework for the safety of CTO for transplantation
  • standards-based approach
  • two-phased strategy

Demand for Standards Background

• National Consensus Conference on Safety of Tissues and Organs (1995)
• Krever Commission Inquiry into the Safety of the Blood System in Canada (1997)
• Parliamentary Standing Committee on Health (1999)
• F/P/T Advisory Committee on Health Services

Canadians have insisted on mandatory national standards for CTO

Standard-Based Regulations Why?

• Balanced representation of stakeholders in development process
• Consensus approach may enhance future compliance
• Written in non-legal/regulatory language
• Easier to update than regulations

National Standards Requirements

• In order for a standard to be recognized as a National Standard it must:
  • be developed through a consensus process
  • be developed by an accredited standards writing body
  • be consistent with or incorporate existing international standards
  • not be written to serve as a barrier to trade or limit innovation or freedom

National Standards Development

• Although numerous sets of standards existed, none met Canadian needs
  • March 1996 - EWG appointed by HC to draft Canadian Standards
  • March 2001 - HC transferred the standards to CSA for further development
  • August 2003 - CSA released the National Standards

National Standards (CSA) Scope

• Serves as a benchmark
  • minimum requirements for verification of safe practice
• Covers entire donation and transplantation process
  • Federal
  • Provincial
  • Practice of medicine
• Safety for potential and actual donors and recipients, personnel and others

CTO Regulations Development

• Standards are made mandatory only when
  • incorporated directly into regulations
  • referenced into regulations
• HC can only use sections of the standards that are
  • under federal authority
  • absolute requirements

CTO Regulations Scope

• Applies to human cells, tissues and organs:
  • for allogenic use
  • that are minimally manipulated*
  • That can be either viable or non-viable

* Phase I heart valves and dura mater will remain under Medical Device Regulations but in Phase II they fall under the CTO Regulations

• Does not apply to cells, tissues and organs:
  • for autologous use
  • that are more than minimally manipulated
  • for assisted reproduction
  • blood and blood products

CTO Regulations Focus of Responsibility

• Source Establishments
  • responsible for 'processing' and distribution
  • banked cells and tissues - deem product suitable/safe for transplant
  • organs - offer product for transplant

CTO Regulations Phase I

• Safety regulations based on the National Standards (CSA)
  • extensive consultations have been undertaken
  • sound cost-benefit analysis completed
• Will also include:
  • Compliance and Enforcement
    • source Establishment, Distributor and Importer for further distribution registration/declaration
  • Adverse Reactions and Errors and Accidents Reporting
    • traceability and reporting to Source Establishment
    • requirements for Source Establishments to report certain AR and E/A to Health Canada

CTO Regulations Phase II

• Build on Phase I requirements
  • maximize the safety of CTO
• Considering:
  • a more comprehensive Compliance and Enforcement strategy
  • a more comprehensive Adverse Reaction and Error and Accident reporting strategy

In the Interim

• Until the new regulations are in place, Health Canada continues to regulate the safety of CTO under the current framework and to address urgent safety issues has:
  • released the Directive and Guidance Document on CTO safety (January 2003)
  • undertaken the National Review of Establishments (March 2003, ongoing)
  • released the Guidance Document of the prevention of SARS transmission (May 2003)
  • released the Guidance Document on prevention of WNV transmission (May 2003 and 2004)

Conclusion

The ultimate goal of the regulatory framework is to balance the need for safe CTO with the need to ensure availability of CTO for transplant

New Regulatory Framework for CTO-Developing a Common Understanding (Part II) Presentation 3 - March 2005

Contact: Policy and Promotion Division

Purpose of this Presentation

• Provide a summary of the Draft Phase I Regulations for CTO to serve as the basis for stakeholder consultation
• It is not intended for consultation on the contents of the Draft Phase I Regulations at this time since it is still under development
• The Proposed Regulations will be published in CG Part 1 for public consultation when it is completed.

Scope of CSA Standards

• CSA Standards cover entire donation and transplantation process which falls within provincial jurisdiction (medical practice) and federal jurisdiction
• Sections of CSA Standards Not Included in the CTO Regulations
  • infection control and safety
  • universal precautions
  • personnel immunization
  • disposal of CTO and human remains
  • informed Consent (with some exceptions)
  • predonation counselling and compensation
  • cross matching
  • transplantation (medical practice)
  • Transplantation Safety Committee

List of CTO in CSA Standards

• Perfusable Organs
  • Heart, kidney, lungs, liver, whole pancreas, stomach, small intestines
• Viable or Non-Viable Cells and Tissues (CT)
  • pancreatic cells (islet cells and other cells derived from pancreas)
  • adipose CT, brain cells, nerve CT;
  • lymphohematopoietic cells (stems cells from bone marrow, cord and peripheral blood; therapeutic cells such as leukocytes for infusion; T-cells such as tumor derived cells; dendritic cells; natural killer cells; cytotoxic lymphocytes;
  • cardiovascular tissues (e.g., heart valves, veins, arteries, aortic and pulmonic conduits, pericardium,)
  • dura mater; fetal, amniotic or placental tissue; connective tissues (fascia)
  • musculoskeletal tissue [e.g., bone (morselized, deminerilized, freeze-dried), cartilage, tendons, joints, and muscle flaps)
  • ocular tissue (cornea and sclera); skin ( full, partial and split-thickness skin grafts)

CTO Regulated Solely Under These Regulations

• Minimally manipulated CTO
  • processing does not alter the original characteristics that are relevant to the CTO utility for reconstruction, repair or replacement (e.g., organs and ocular tissues)
• Viable or nonviable
• Intended for allogeneic use

CTO Covered Under Other Regulations

• More than minimally manipulated
• Currently subject to other regulations for drugs (e.g., blood, semen) or medical devices (e.g., heart valves, dura mater, wound dressing containing live cells, demineralized bone)
• Intended for use in investigational studies or clinical trials in humans (e.g., certain cellular therapies, genetically modified cells)
• Is combined with non-tissue products, including drugs and devices
• Meets other criteria (following criteria under consideration and requires further discussion)
  • intended for non-homologous use
  • has a systemic effect

Activities Covered Under These Regulations

Primary Activities

• Processing (applies to source establishments)
  • donor screening and testing (serological tests)
  • CTO retrieval/collection
  • laboratory testing (microbiological and other tests)
  • preparation, preservation and evaluation
  • quarantine
  • banking (storage for further distribution)
  • packaging and labelling
  • release for distribution
• Distribution of domestic CTO
• Importation of CTO for further distribution
• Secondary Activities (applies to other establishments, including transplant establishments)
  • adverse events reporting
  • error/accident reporting
  • product removal from chain of distribution
  • record-keeping and tracking
  • exceptional release
• Quality Assurance System (applies to primary and secondary activities)
• Transitional Provisions

Establishments Covered Under These Regulations

• Source Establishments: responsible for "processing" and release of suitable/safe CTO for transplantation)
  • examples of source establishments
  • Organ Donation Organization for organs from a deceased donor
  • Transplant Establishment for organs and fresh cells from a live donor
  • Cell/Tissue Bank for cells and tissues stored for further distribution
• Distribute domestic CTO (Could be source establishment or other establishment)
• Import CTO for further distribution

Prohibition and Registration

• Prohibition
  • prohibits establishments from importing or distributing CTO unless they are processed and distributed in accordance with these Regulations
• Registration
  • specifies which establishments need to register
  • application filed with the Minister

Processing: General

• Must use validated processes and procedures to process CTO
• Prohibition of CTO pooling from different donors during processing, except for lymphohematopoietic cells
• Source establishment has oversight of processing activities it carries out itself or carried out on its behalf

Processing: Donor Assessment - Screening

• Documentation of donor information and history
• Determination of donor suitability on the basis of the contraindications or exclusion criteria set out in the CSA standards

Processing: Donor Assessment - Testing

• Minimum donor serological tests as specified in general and subset CSA Standards
• Application of hemodilution algorithm

Processing: Retrieval and Laboratory Testing

• Maximum time limits between cardiac asystole and the retrieval of tissues specified in SOPs
• Bacteriological testing as specified in the CSA standard

Processing: Storage and Banking

• Storage in secure location under appropriate conditions
• Segregation of autologous and allogeneic CTO during storage
• Segregation of CTO from untested/positive donors and those from negative donors
• Storage of archived serum samples from tissue donors
• Establishment of expiry dates for banked cells and tissues
• Determination of maximum storage periods for organs and cells that are not banked

Processing: Quarantine and Release

• CT must be quarantined until it is determined that it has been processed according to all the regulatory requirements
  • investigation of any error/accident or adverse reactions and corresponding incidents is complete
  • where applicable, CT from live donors have been quarantined for a minimum of 180 days and the donor retested (does not apply to lymphohematopoietic cells)
  • evaluation performed to determine suitability prior to release and distribution

Processing: Labelling and Packaging

• Must label in a manner that protects donor confidentiality
• Specifies information that must be provided on the interior label, package insert and the exterior label for different CTO
• Packaging materials must be approved for the intended use
• Must determine the appropriate way to package, inspect, label, and transport each type of CTO
• Must verify the shipment with the receiving establishment.

Exceptional Release

• Criteria for exceptional release will be included in Phase I of the regulations

Adverse Reaction (AR) Reporting and Investigation

• Specifies the requirements for adverse reaction reporting and investigation

Error/Accident (E/A) Investigation

• Specifies the requirements for E/A investigation and reporting

Record Keeping

• Source establishment must assign a donor identification code to each donor and ensure the code is a component of its records.
• Records must be kept by all establishments in a manner that enables tracing of all CTO from the donor to the recipient while maintaining donor and recipient confidentiality
• Includes requirements for records creation, storage, retrieval and archival
• Specifies information to be included in the donor and recipient records
• Other establishments must provide source and transplant establishments with information required to complete the donor and recipient records

Personnel and Facilities

• An establishment must have sufficient qualified and trained personnel, with ongoing training, and competency evaluation
• Contains criteria for facility construction, maintenance, and access

Equipment and Material

• Criteria for equipment maintenance and validation
• Criteria for materials used in processing of CTO

Quality Assurance (QA) System:

• Every establishment that processes or distributes CTO must have a QA system that complies with the requirements of these Regulations
• Every establishment must have SOPs for all activities
• Establishments must conduct an internal audit/ self-inspection at specified intervals to verify that its activities comply with these Regulations and its SOPs

Transitional Provisions - General

• CT that were processed before the coming into force of the Regulations may be distributed under specified conditions:
  • if they do not meet the donor suitability assessment, or when serological testing results were incomplete
  • may be subject to exceptional release if they do not meet the transitional provisions

Regulatory Approach

• In general, the Proposed Regulations contain broad goals that are applicable to a wide range of CTO (i.e., specifies what but not how)
• Establishments have the flexibility to determine how to meet these goals by developing specific requirements for the CTO they process

Introduction to Adverse Reaction Reporting Presentation 4a March 2005

Contact: Policy and Promotion Division

Role of Health Canada

Health Canada is responsible for post-approval surveillance and assessment of signals and safety trends concerning marketed health products.

Rationale

Monitoring Health Product Safety data such as adverse reaction reports, conducting risk/ benefit assessments and recommending appropriate regulatory action when problems are identified.

Authority

The legislative requirements for the post approval surveillance of health products are covered under the Food and Drugs Act and Regulations.

Definition of Adverse Reaction

Adverse reaction - any unintended or untoward response to any cell, tissue or organ for which there is a reasonable possibility that the response may have been caused by the transplant (i.e. the relationship cannot be ruled out).
(CSA Standards Z900.1-3)

Definition of Serious Adverse Reaction

An adverse reaction which:

1. results in in-patient hospitalization;
2. results in prolongation of existing hospitalization;
3. results in persistent or significant incapability (including transmission of a disease or failure of the transplant's function or integrity);
4. is life-threatening; or
5. results in death.

Adverse Reactions (AR)

• AR affect the patient (recipient)
• AR occur after transplantation

Adverse Reactions: examples

• Transmission of an infectious disease
• Transmission of cancer
• Immune reactions
• Unexpected death

Health Products Adverse Reaction mandatory reporting to Health Canada

Currently, federal regulations set the requirements for the manufacturers to report adverse reactions for the following health products:

• Drugs
• Natural Health Products
• Blood
• Semen
• Medical Devices

Timelines for reporting adverse reactions may vary according to the product and the level of risk involved for example: 15 days for serious adverse reactions to drugs but 24 hours for a death following blood transfusion

While this consultation is about which CTO adverse reactions should be subject to mandatory reporting to the federal level, any adverse reaction can be voluntarily reported to Health Canada.

What does Health Canada do with adverse reaction reports?

• Information on suspected adverse reactions is collected and monitored
• Safety information (from AR reports and other sources) is analyzed
• Product related risks are communicated to health care professionals and the public
• Regulatory actions are used, when necessary, which may include removal of a product from the market.

What Feedback is Provided to Reporters?

• Acknowledgement letters
  • unique tracking number assigned to facilitate matching follow-up information to original report
• Health Canada Risk Communications
  • Canadian Adverse Reaction Newsletter
  • Advisories

Health Canada Risk Communications

To receive the Canadian Adverse Reaction Newsletter and health product Advisories by e-mail, join Health Canada's Health_Prod_Info mailing list: Advisories, Warnings and Recalls

Introduction to Error and Accident Reporting Presentation 4b - March 2005

Contact: Policy and Promotion Division

Errors and Accidents

• E/A occur during the process
• E/A affect (or could affect) the product (CTO) and therefore the patient
• E/A occur before transplantation

Error vs Accident

• Error - an unexpected or unplanned deviation from standard operating procedures or applicable laws and regulations that could adversely affect the safety, efficacy or quality of the product or adversely affect the recipient or the facility personnel
• Accident - an unexpected or unplanned event, not attributable to a deviation from standard operating procedures or applicable laws or regulations, that could adversely effect the safety, efficacy or quality of the product or adversely affect the recipient or the facility personnel

Error vs Accident: examples

Error:

• Donor testing not performed according to manufacturer's instructions
  • Incubation times not respected
• Applying the wrong label to a product

Accident:

• Donor information provided after donor suitability assessment performed
  • Travelled to a SARS endemic area

Reporting to Health Canada

Currently, federal regulations set the requirements for manufacturers to report the following health products:

• Drugs (recall)
• Natural Health Products (recall)
• Blood (E/A)
• Semen (incident)
• Medical Devices (recall and mandatory problem reporting)
• Timelines for reporting may vary according to the product and the level of risk involved for example:
  • 30 days for a medical device incident that could, but did not, seriously affect the health of a patient

• versus
  • within 24 hours for an E/A that could affect the safety of the blood system

What does Health Canada do with these reports?

• Used in health hazard evaluation (assessing the hazard posed by a health product and the likelihood or risk of the hazard recurring, based on available information)
• Used in Risk-Benefit Assessment (weighs the potential risks or hazards associated with a product against the benefits of that product to a specific individual or population)
• Based on the level of risk
  • May request a recall (may monitor the recall by doing an effectiveness check)
  • Monitor the firm's investigation of the situation

What is a recall?

A recall is a set of actions taken, by a firm (source establishment, importer or distributor), to remove from the market a product (CTO) which represents a health risk for Canadians or which contravenes the Food and Drugs Act and Regulations.

What Feedback is Provided to Reporters?

• Health Canada Risk Communications
  • Acknowledgement letters
  • Releasing warnings/advisories on drugs, medical devices, and natural health products

Errors and Accidents vs Adverse Reactions

• E/A can lead to adverse reactions
• The investigation of an adverse reaction can lead to discover an E/A

Adverse Reaction and Error and Accident Reporting for Cells, Tissues and Organs: Phase I Presentation 5

Contact: Policy and Promotion Division

March 2005

Definition of Adverse Reaction

Adverse reaction - any unintended or untoward response to any cell, tissue or organ for which there is a reasonable possibility that the response may have been caused by the transplant (i.e. the relationship cannot be ruled out). (CSA Standards Z900.1-3)

Phase I Suspected Adverse Reactions Reporting Between Establishments

All establishments including transplant establishments will be obliged to report all suspected adverse reactions to the source establishment that processed the CTO.

Phase I Requirements (CTO) for Source Establishments

The source establishment will have to investigate suspected adverse reactions and take corrective action based on the results of the investigation.

Phase I Requirements (CTO) for all establishments

All establishments contacted by a source establishment conducting an investigation have a responsibility to assist in the investigation and provide all relevant information to the source establishment.

Phase I Adverse Reaction Reporting to Health Canada

The source establishment will be required to report to Health Canada (HC) all instances of infectious disease transmission suspected to be attributable to the use of cells, tissues or organs

Caveat

• HC needs this information to monitor the safety of these products (cells, tissues and organs) and fulfill its obligations as a regulator.
• This reporting in no way replaces the current mandatory reporting of infectious diseases to Public Health authorities.
• Both reporting systems will continue to operate.

Definition of Error

Error - an unexpected or unplanned deviation from standard operating procedures or applicable laws and regulations that could adversely affect the safety, efficacy or quality of the CTO or the recipient or the facility personnel.

Definition of Accident

Accident - an unexpected or unplanned event, not attributable to a deviation from standard operating procedures or applicable laws or regulations, that could adversely effect the safety, efficacy or quality of the CTO or the recipient or the facility personnel.

Phase I Requirements (CTO) for Source Establishments

The source establishment will have to investigate error and accidents (E/A) and take corrective action based on the results of the investigation.

Phase I Requirements (CTO) for all establishments

All establishments contacted by a source establishment conducting an investigation have a responsibility to assist in the investigation and provide all relevant information to the source establishment.

Phase I E/A Reporting to Health Canada

The source establishment will be required to report to HC any E/A that could lead to the transmission of an infectious disease/agent.

Proposed Options for Adverse Reaction and Error Accident Reporting in Phase II Presentation 6 - March 2005

Contact: Policy and Promotion Division

Adverse Reaction Reporting

• Under Phase I all adverse reactions are to be reported to the source establishment.
• The source establishment will be responsible for investigating these reports.
• Under Phase I, source establishments will report all instances of infectious diseases transmission to HC

What else is required?

• The Phase I requirements are the minimum needed to reduce risks to the system.
• There may be other adverse reactions that HC should be made aware of to reduce the risks inherent in the system.

Issues for Consideration

• Some adverse reactions may need to be reported when they are only suspected.
• Some adverse reactions may need to be reported only when confirmed.
• Some adverse reactions may need to be reported immediately.
• Some adverse reactions may need to be reported monthly, or yearly.

Proposed Options for Adverse Reaction Reporting

• Option 1: Source establishment reports to HC all serious adverse reactions caused by the transmission of an infectious disease.
  • This option would maintain the status quo established by the Phase I of the regulations.
• Option 2: Source establishment reports to HC all serious adverse reactions caused by the transmission of infectious or non-infectious disease.
• Option 3: Source establishment reports to HC all adverse reactions caused by the transmission of an infectious or non-infectious disease.
  • This option therefore covers both serious and non-serious adverse reactions.

E/A reporting to Health Canada

• Under Phase I, the source establishment:
  • Will be responsible for investigating E/A reports
  • Will be required to report to HC any E/A that could lead to the transmission of an infectious disease/agent

What else is Required?

• The Phase I requirements are the minimum needed to reduce risks to the system.
• There may be other E/A that HC should be made aware of to reduce the risks inherent in the system.

Proposed Options for E/A Reporting

• Option 1: Source establishment reports to HC all E/A that could lead to the transmission of an infectious disease/agent
  • This option would maintain the status quo established by the Phase I of the regulations.
  • e.g. transmissible disease testing using expired reagents
• Option 2: Source establishment reports to HC all E/A that could cause any serious adverse reaction
  • This option therefore covers not only the E/A that could lead to infectious disease transmission but also those that could lead to other (non-infectious) serious adverse reactions.
  • e.g. HLA miss-typed
• Option 3: Source establishment reports to HC all E/A that could cause any adverse reaction.
  • This option therefore covers the E/A that could lead to both serious and non-serious adverse reactions.
• Option 4: Source establishment reports to HC all error/accidents
  • This option therefore covers all E/A , whether they have the potential to lead to adverse reactions or not . The timing of the reports could vary with the type of E/A to be reported, with a system agreed to for yearly reports in some cases, or monthly reports for other types etc.
  • e.g. storage temperature not maintained

Introduction to Compliance Monitoring and Enforcement Presentation 7

Contact: Policy and Promotion Division

March 2005

HPFB's Role in Compliance Monitoring and Enforcement

To deliver a national compliance monitoring and enforcement program for all products under the mandate of the HPFB (except food) while supporting

• the risk management approach to decision-making; and
• the vision of a comprehensive regulatory strategy across all product classes.

Authority

• The Minister of Health has the responsibility for compliance with and enforcement of relevant legislation and regulations.
• This responsibility is discharged on a day-to-day basis by HPFB who administers relevant legislation.
• On reasonable grounds, an Inspector can enter a place to
  • examine and take samples
  • open and examine packaging
  • examine and make copies
  • seize and detain

(Section 23 Food & Drugs Act)

Compliance and Enforcement Policy

Purpose:

• To provide guiding principles for the fair, consistent and uniform application and enforcement of relevant Acts and Regulations.
• To increase transparency by providing the industry with a clear description of the Inspectorate's role in delivering a national compliance monitoring and enforcement program.

  Compliance and Enforcement Policy (POL-0001)

Compliance Monitoring and Enforcement Policy - Guiding Principles

• Transparency
  • C&E Policy is a public document
  • Make information on our activities available
• Fairness
  • Applied in a fair and equitable manner
  • Predictable and uniform national approach
  • Non discriminatory and unbiased
• Based on Risk Management
  • Decision based on level of risk
  • Directed at the earliest point of distribution
• Qualified Staff
  • Adequate training
• Commitment to Quality Policy

Compliance Promotion Activities

• Education
  • Encourage compliance through education.
• Consultation
  • Encourage industry and other stakeholders to participate in the development of all health and safety standards and will strive to consult with industry on legislative, regulatory, and policy issues.
• Information
  • Provide information to consumers to enable them to be active participants in maintaining their health and the safe use of marketed products.

Compliance Monitoring Activities

• Voluntary Compliance Programs
  • HC may negotiate formal and informal commitments with industry associations or regulated parties.
• Inspections
• Samplings and Analyses
• Compliance Verification and Investigation
  • Where HC identifies or is notified of a potential problem.

Responses To Non-Compliance

• Voluntary Disposal
• Voluntary Detention
• Recall
• Negotiated Compliance
• Warning
• Stop Sale
• Customs Look-Out/Alert
• Import Refusal
• Suspension or Cancellation of Marketing Authorization/Product Licence
• Suspension or Amendment of Establishment Licence
• Formal Hearing
• Seizure and Detention
• Prosecution
• Injunction

Compliance Monitoring and Enforcement For Other Products

• Medical Devices
  • 4 risk-based classes of devices. Class II, III and IV need to be licenced.
  • Establishment licence: attestation that records and procedures are maintained / Distribution, complaints, recalls and mandatory reporting is required.
  • All importers and distributors and Class I manufacturers must have an EL.
  • Retailers, health care facilities and manufacturers of Class II, III and IV devices do not require an Establishment Licence (EL).
• Drugs (excluding Natural Health Products)
  • All drugs must meet the Food & Drugs Act (F&DA) and Regulations.
  • All drug manufacturers must meet the F&DA Good Manufacturing Practice (GMP) Regulations.
  • National inspection program currently exists
• Natural Health Products (NHPs)
  • All NHPs must meet the F&DA and the Natural Health Products Regulations.
  • Self attestation.
  • No inspection program.
• Blood
  • Considered a drug under Food & Drug Regulations.
  • Under national inspection program blood establishments inspected annually.
  • New regulatory framework under development.
• Semen
  • Considered a drug under Food & Drug Regulations.
  • Notification.
  • National inspection program currently exists.
• CTO
  • National Review currently underway.

For more on Compliance Monitoring and Enforcement

Compliance Monitoring and Enforcement Phase I of the CTO Regulations Presentation 8 - March 2005

Contact: Policy and Promotion Division

Outline

• Compliance Monitoring and Enforcement (C&E)
• The National Review
• Phase I of CTO Regulations

Compliance Monitoring and Enforcement Actions

• C&E actions are based on principles of risk management and aimed at intervening at the earliest point of distribution to achieve the greatest impact and efficiency.

  Compliance and Enforcement Policy (POL-0001)

• The selection of C&E actions and their sequencing, may include the following:
  • voluntary disposal;
  • voluntary detention;
  • warning letter;
  • import refusal;
  • seizure and detention;
  • public warnings; and
  • public advisories/letters to associations.

Compliance Monitoring and Enforcement Considerations

• HC takes into account the following:
  • the risk to health and safety of the recipients;
  • the need to balance the safety of the product with the need to ensure availability of product;
  • the likelihood that the same problem will reoccur; and
  • the need to maintain public confidence in the programs administered by HC.

National Review Interim Measure

• January 2003: Issuance of HC Directive entitled "Technical Requirements to address the Safety of CTO for Transplantation and its corresponding Guidance Document entitled "Basic Safety Requirements for Human Cells, Tissues and Organs for Transplantation"
  • basic safety requirements
• March 2003: HC initiated a National Review, with the issuance of compliance letters to 143 known programs in 53 Canadian establishments.

National Review Objective

• To assess establishments' adherence to basic safety requirements in addition to taking appropriate actions to prohibit the distribution of unsafe products.
• Ongoing

National Review C&E Policy

• HC developed a C&E policy for the safety of CTO
• The main objectives of this policy are:
  • to minimize the health risks associated with the use of CTO; and
  • to foster transparency of the compliance monitoring and enforcement actions that can be taken by HC

National Review 2 Stages

• Documentation assessment stage
  • Documentary evidence to demonstrate their adherence to basic safety requirements
    • to comply with sections 8 and 19 of the Food and Drugs Act.
• Compliance Inspection stage
  • HC visits establishments to assess their adherence to basic safety requirements.

National Review Documentation Assessment Stage

• HC has contacted establishments thought to be involved in the handling and/or processing of CTO that fall under the scope of the Directive.
  • these include surgical bone banks, tissue banks, cord blood banks, eye banks, stem cell programs, organ donation organizations, and importers.
• As of February 15, 2005, HC has issued compliance letters to a total of 189 programs within various establishments
• The documentation received from CTO programs is assessed for adherence to basic safety requirements based on four critical elements:
  • serological testing
  • bacteriological testing
  • donor suitability assessment
  • sterilization

National Review Compliance Inspection Stage

• Using a risk-based approach
  • The inspections focus on, but may not be limited to, four screening elements:
    • serological testing
    • bacteriological testing
    • donor suitability assessment
    • sterilization

CTO Regulations

• The intent is to have a 2-phase approach to the implementation of the new regulations. In terms of compliance monitoring and enforcement:
  • Phase I: Requirement to Register
  • Phase II: Build on the requirements of Phase I to include a more comprehensive Compliance Monitoring and Enforcement Strategy, as required.

Phase I - Registration Requirements

• A written application must be made to the Minister by:
  • Any establishment that processes, or distributes CTO.
  • Any establishment, except a transplant establishment, that distributes or imports CTO for further distribution.

Phase I - Registration Application

• Application for registration will contain:
  • description of type of CTO imported, processed or distributed
  • description of the types of activities that the establishment carries out or for which it is responsible
• A declaration of compliance signed by:
  • Medical Director; or
  • Scientific Director

Phase I - Registration Number

• Minister will issue a registration number to the establishment
  • if satisfied with the information provided
• Registration number is valid for two years.

Phase I - Ministerial Powers

• Refusal to issue registration number
• Suspension or revocation of registration number
• Request additional information
• Refusal to issue registration number
  • if there is reason to believe that any of the information provided is false, misleading, inaccurate or incomplete
• Suspension or revocation of registration number:
  • if there is reason to believe that
    • Establishment is not in compliance with the CTO regulations
    • There has been a change in any of the information provided by the establishment in the application
• Request additional information:
  • Establishment must provide any additional information to demonstrate that the activities it carries out are in compliance with the CTO Regulations

Phase I - Notification Requirements

• Must notify the Minister of any change in the information provided in its application for registration
• Must notify the Minister if you stop importing, processing or distributing CTO

Proposed Options for Compliance Monitoring and Enforcement in Phase II Presentation 9 - March 2005

Contact: Policy and Promotion Division

Objectives

• The C&E scheme provides HC with:
  • a means of staying abreast of what CTO facilities exist
  • what activities they are engaged in; and
  • a mechanism to verify information (compliance verification)

Considerations

• Risk based strategy
  • a strategy that includes a variety of tools, where the specific tool(s) used depends upon the risk associated with the activity being regulated.
• Voluntary (3rd Party) standards
  • will standards and accreditation be considered equivalent?
• Current tissue processing
  • variations in how tissues are currently processed
  • establishments at different stages in revising their processes
• Provincial jurisdictions
  • primary role in healthcare activities and legal concerns relating to CTO donation and transplantation
• Semen regulations experience
  • C&E strategy was not developed before regulations were introduced
  • high percentage that had attested compliance were in fact not compliant
  • national inspection program

• U.S. FDA approach to human cellular and tissue products (HCT/P)
  • Registration of facilities
    • Administrative information
    • List of HCT/P
  • Does not constitute a determination of compliance with the regulations

Options for Phase II

1. Registration (status quo)
2. Establishment licensing based on application
3. Establishment licensing based on HC inspection
4. Establishment licensing based on third party inspection

1. Registration (Status Quo)

• A written application must be made to the Minister
  • type of CTO imported, processed or distributed
  • types of activities carried out or for which the establishment is responsible for
  • a declaration of compliance
  • Minister will issue a registration number to the establishment, if satisfied with the information provided
  • registration number is valid for two years
• HC Considerations
  • HC will know which establishments are involved in the handling of CTO.
  • CTO establishments can start or continue operations with minimal delay.
  • contrary to the Krever recommendation.
  • may not be sufficient to minimize risk.

2. Establishment Licensing Based on Application

• Source establishments, importers and distributors could be required to obtain an EL
  • Application to the Minister, as per registration
  • Plus additional information, such as:
    • SOP for critical control points
    • Donor suitability assessment forms and questionnaires
    • Self audit documentation
• Considerations
  • HC will know which establishments are involved in the handling of CTO.
  • Greater ability to detect and to manage risks before an adverse event occurs.
  • Consistent with the Krever recommendations.
  • Consistent with other compliance and enforcement tools used for other therapeutic products.
  • Could utilize existing compliance/enforcement systems and resources.

3. Establishment Licensing Based on Health Canada Inspection

• EL could be dependent upon an inspection
  • Inspections
    • a sampling of records
    • descriptions of the processes or procedures
    • it may also be necessary for the inspector to observe processes first hand.
• Considerations
  • HC will know which establishments are involved in the handling of CTO.
  • Greater ability to detect and to manage risks before an adverse event occurs.
  • Highest level of control/assurance by federal government.
  • Could utilize existing compliance/enforcement systems and resources.
  • Consistent with the Krever recommendations
  • Consistent with the treatment of other therapeutic products under the F&DA.

4. Establishment Licensing Based on Third Party Accreditation

• There are 2 possible scenarios:
  • Accept an accreditation as being equivalent to meeting the F&DA and CTO Regulations
    • Accreditation would be mandatory to obtaining an EL
  • HC would authorize a third party to assess compliance with the F&DA and CTO Regulations
    • Third party information would be submitted (i.e. reports from external inspectors, proof of an equivalent accreditation)
    • HC would then make the ultimate decision regarding compliance.
• HC is currently researching the viability of such scenarios
• Considerations
  • HC will know which establishments are involved in handling CTO.
  • Greater utilization of more varied experience.
  • Need to clarify responsibilities and accountabilities.
  • Need to set up an accreditation system for CTO.
  • May be costly for the CTO community.
  • Evaluation/assessment conducted by peers who are in the field.
  • Hospital - based programs already familiar with accreditation

Health Canada Authority

• HC will retain the right to inspect, perform compliance verification, and investigate

Conclusion

• Why is C&E important?
  • Self regulation
    • e.g. Semen regulation
    • High percentage that had attested compliance were in fact not compliant

Next Steps and Evaluation

Contact: Policy and Promotion Division

Next Steps Phase I

• Drafting Phase
• Canada Gazette I
  -75 day consultation period
• Canada Gazette II
  -Regulations enacted

Next Steps Phase II

• Consultation Report
• Review of Legal Authority
• Cost Benefit
• Drafting
• Canada Gazette I
  -75 day consultation period
• Canada Gazette II
  -Regulations enacted

Evaluation

• Yellow forms

Participant Workbook Cells, Tissues and Organs Regulatory Framework -- Phase II Adverse Event Reporting
DAY 1

Contact Policy and Promotion Division

Introduction

A new regulatory framework is being proposed under the Food and Drugs Act (F&DA), to regulate all establishments and individuals in Canada that handle and/or process human cells, tissues and organs (CTO) for transplantation. These new regulations will address safety in the manufacture and use of minimally manipulated products and will be introduced using a two-phased approach. Phase I is recognized as the implementation of the Canadian Safety Standards into regulation, including requirements for adverse event reporting and investigation of adverse events. Phase II will build on the requirements instituted in Phase I, as necessary, in order to develop more comprehensive compliance monitoring and adverse event reporting systems.

The Issue

Health Canada has the authority under the F&DA to implement a mandatory adverse event reporting system. Phase I of the regulatory framework for CTO will include several requirements for the investigating and reporting of adverse events. Phase II of the framework will provide an opportunity to amend the regulations to build on Phase I requirements, as necessary, in order to maintain an appropriate level of adverse event reporting. Determining the approach for Phase II can best be done after consulting with stakeholder groups on the adverse event reporting options being considered.

Background: Phase I Requirements

Phase I of the regulatory framework for CTO will include several requirements for the investigating and reporting of adverse events. All establishments have a responsibility to report adverse events, including confirmed or suspected adverse reactions and error/accidents, to the source establishment that processed the CTO. Similarly, all establishments contacted by a source establishment conducting an investigation have a responsibility to assist in the investigation and provide all relevant information to the source establishment.

The primary responsibility for investigation and reporting to Health Canada falls upon the source establishment. The source establishment is uniquely situated in the supply chain to be best able to conduct investigations and report to all other establishments, as required under the regulatory framework, as well as provide any necessary reports to Health Canada. The source establishment will be required to report to Health Canada any suspected transmission of infectious disease/agent so that Health Canada can fulfill its obligations as the regulator. The source establishment will also be required to report any error or accident that could lead to the transmission of an infectious disease/agent.

Note: All Phase II options refer to obligations on the source establishment. It is anticipated that no new requirements will be placed on other establishments.

Options for Phase II: Proposed Adverse Event Reporting

Phase II of the framework will provide an opportunity to amend the regulations to build on the Phase I requirements as necessary in order to maintain an appropriate level of adverse event reporting. The following proposed options for adverse event and error/accident reporting by source establishments are being considered for Phase II.

Adverse Reaction Reporting Options:

Option 1: Source establishment reports to Health Canada all serious adverse reactions caused by the transmission of an infectious disease/agent. (Status Quo)

Under Phase I of the proposed CTO Regulations, source establishments are required to report to Health Canada all suspected instances of infectious disease/agent transmissions attributable to the transplanted CTO. This option would maintain the status quo established by the Phase I regulations after they come into effect.

Option 2: Source establishment reports to Health Canada all serious adverse reactions caused by the transmission of an infectious or non-infectious disease or disease agent.

In addition to the requirements under Phase I of the proposed CTO regulations (ie the reporting of all suspected instances of infectious disease/agent transmission to Health Canada), source establishments will be required to report to Health Canada the transmission of diseases/agents that caused the serious adverse reactions. Reporting of disease/agent transmissions would be restricted to instances that could be attributable to the transplanted CTO, and would include both infectious and non-infectious disease/agent transmission. Depending on the disease/agent and its nature, some reporting would occur when the transmission is only suspected, while other reporting could be delayed until the transmission was confirmed.

Option 3: Source establishment reports to Health Canada all adverse reactions caused by the transmission of an infectious or non-infectious disease/agent.

In addition to the requirements under Phase I of the proposed CTO regulations (ie the reporting of all suspected instances of infectious disease/agent transmission to Health Canada), source establishments will be required to report to Health Canada the transmission of diseases /agents that caused the adverse reaction. Reporting of disease transmission would be restricted to instances that could be attributable to the transplanted CTO, and would include both infectious and non-infectious disease/agent transmission. Depending on the disease/agent and its nature, some reporting would occur when the transmission is only suspected, while other reporting could be delayed until the transmission was confirmed.

Error/Accident Reporting Options:

Option 1: Source establishment reports to Health Canada all errors/ accidents that could lead to the transmission of an infectious disease/agent (Status Quo).

Under Phase I of the proposed CTO regulations, source establishments will be required to report all errors/accidents that may cause the transmission of an infectious disease/agent. This option would maintain the status quo established by the Phase I regulations after they come into effect.

Option 2: Source establishment reports to Health Canada all error/accidents that could cause any serious adverse reaction.

This option would require source establishments to report all error/accidents to Health Canada that may result in any type of serious adverse reaction.

Option 3: Source establishment reports to Health Canada all error/accidents that could cause any adverse reaction.

This option would require source establishments to report all error/accidents to Health Canada that may result in any type of adverse reaction.

Option 4: Source establishment reports to Health Canada all error/accidents.

All error/accidents would be reported by the source establishment to Health Canada. The timing of the reports could vary with the type of error/accident to be reported, with a system agreed to for yearly reports in some cases, or monthly reports for other types etc.

Adverse Reactions

1a) Are there adverse reactions that must be reported immediately to Health Canada, even if they are only suspected to be related to the CTO? If so, please give examples?

1b) Are there adverse reactions that should be reported to Health Canada, but only after they have been confirmed to be related to the CTO? If so, please give examples.

1c) Are there adverse reactions that could be reported to Health Canada at a later date, for instance, by way of monthly, quarterly, yearly (etc.) reports? If so, please give examples.

Error/Accidents

2a) Are there error/accidents that must be reported immediately to Health Canada? Can you give examples?

2b) Are there error/accidents that could be reported to Health Canada at a later date, for instance, by way of monthly, quarterly, yearly (etc.) reports? If so, can you give examples?

Adverse Reaction Reporting Options

3a) Please rank the options for Phase II adverse reaction reporting from most desirable/acceptable to least desirable/acceptable (1=most desirable/acceptable; 3=least desirable/acceptable).

Source establishment Reports to Health Canada

• all serious adverse reactions caused by the transmission of an infectious disease/agent (Status Quo)
• all serious adverse reactions caused by the transmission of an infectious or non-infectious disease/agent.
• all adverse reactions caused by the transmission of an infectious or non-infectious disease/agent.

3b) Please explain your rational for your choice of the most desirable option? Please include benefits and detriments to having the choice implemented.

Error/Accident Reporting Options

4a) Please rank the options for Phase II error/accident reporting from most desirable/acceptable to least desirable/acceptable (1=most desirable/acceptable; 4=least desirable/acceptable).

• Source establishment Reports to Health Canada
• all errors/accidents that could lead to the transmission of an infectious disease/agent (Status Quo)
• error/accidents that could cause any serious adverse reaction
• all error/accidents that could cause any adverse reaction
• all error/accidents

4b) Please explain your rationale for choosing the most desirable option. Please include benefits and detriments to having the choice implemented.

Participant Workbook Cells Tissues and Organs Regulatory Framework - PHASE II Compliance and Enforcement Monitoring
(Day Two)

Contact Policy and Promotion Division

Introduction

A new regulatory framework is being proposed under the Food and Drugs Act (F&DA), to regulate all establishments and individuals in Canada that handle and/or process human cells, tissues and organs (CTO) for transplantation. These new regulations will address safety in the manufacture and use of minimally manipulated products and will be introduced using a two-phased approach. Phase I is recognized as the implementation of the Canadian Safety Standards into regulation. Phase II will build on the requirements instituted in Phase I, as necessary, in order to develop more comprehensive compliance monitoring and adverse event reporting systems.

Issue

Health Canada is responsible for delivering a national compliance monitoring and enforcement program for all health products. To develop such a program for Phase II of the CTO Regulations, the most effective risk-based mechanism should be identified. This can best be done after consulting with stakeholder groups on the compliance monitoring and enforcement options being considered.

Options for Phase II

The compliance monitoring and enforcement scheme that accompanies the CTO Regulations must achieve two things:

• It must provide Health Canada with a means of staying abreast of what CTO facilities exist and the activities they are engaged in. This information will, in turn, allow for risk assessment.
• It must provide Health Canada with a mechanism to verify information that is gathered through the identification process; that is, a means by which to assess compliance.

The following proposed options for the compliance monitoring and enforcement that are being considered for Phase II include the following:

Option 1
Registration

A registration scheme is proposed in Phase I, and there may be activities for which this scheme is sufficient in Phase II. During registration, a number of items may be requested from the establishment including:

• the establishment's administrative information, such as address, contact person, etc.
• a detailed description of the types of cells, tissues and organs that it imports, processes or distributes;
• a description of the types of processing or distribution activities that it carries out or for which it is responsible, and, in the case of storage, the period during which the establishment has banked cells or tissues; and
• a statement dated and signed by the medical director or scientific director certifying that the establishment is in compliance with regulations.

The Minister may request additional information, such as standard operating procedures, donor screening questionnaires, testing protocols, etc., to demonstrate that the activities carried out are in compliance with the regulations.

For other higher risk activities, it may be necessary to move beyond registration, to a system in which tools are based on risk. A variety of tools are explored below; a list of considerations associated with all options is included in Appendix A.

Option 2
Establishment Licensing Based on Application

Under this option, establishments responsible for retrieval and collection, screening, testing, preservation, packaging, labeling, storage and/or distribution could be required to obtain an Establishment License (EL).

To do so, an application would have to be submitted to the Minister providing the information required for registration, and additional information, at the time of application. Additional information could include:

• standard operating procedures for critical control points;
• donor suitability assessment forms and questionnaires; and
• self audit certificates/documents.

Upon receipt of the application, the Minister may require that an inspection be conducted of any of the activities identified on the application.

Option 3
Establishment License Based on Health Canada Inspection

Obtaining an EL could be dependant upon an inspection by Health Canada inspectors. Inspections would involve requesting a sampling of the establishment's records, and descriptions of processes or procedures, to assess compliance; it may also be necessary for the inspector to observe processes first hand.

Option 4
Establishment License Based on Third Party Inspection

If Health Canada were to involve third parties in verifying compliance on site, there could be several possible approaches. In each scenario, Health Canada would retain the right to inspect, perform compliance verification and investigate.

1. Health Canada could accept an accreditation from another organization as being equivalent to meeting the F&DA and CTO Regulations. Under such a scheme, accreditation by this external organization would be mandatory to obtaining an EL from Health Canada.
2. A second possibility could be a designation-based scheme, under which Health Canada would authorize a third party to assess compliance with the F&DA and CTO Regulations. Health Canada could then have third party information submitted (i.e. reports from external inspectors, proof of an equivalent accreditation) and make the ultimate decision regarding compliance internally.

Health Canada is currently researching the viability of such scenarios.

Recent Developments

In January of 2003, Health Canada released a Directive and Guidance Document, and in May 2003 CTO National Standards were published. Both recommended that certain minimum safety requirements for the processing of CTO be followed.

1. What has been the impact on your organization of the Directive and Guidance Document and the National Standards ?

General CTO Discussion

Regulation for the CTO community has been endorsed by stakeholders and government, and Health Canada is now in the process of developing a regulatory framework.

2. In your view, what are the benefits/concerns of such regulation?

3. In developing the regulatory framework, what do you see as the benefits/concerns of a strategy where the compliance monitoring and enforcement tools used are dependent on risk of the activities involved? What would be an alternative(s)?

Tissues - Options Analysis

4.a) Please rank the compliance monitoring and enforcement options according to appropriateness/effectiveness with respect to tissues.

Source

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

Importers, Distributors

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

4b) Please explain your ranking for tissues and what the benefits/drawbacks of your preferred tool may be.

5. Are there any specific tissue-related activities that would be better regulated by a tool other than that which you have ranked first? (Please refer to 'processing' in glossary for list of activities.)

Organs

6.a) Please rank the compliance monitoring and enforcement options according to appropriateness/effectiveness with respect to organs.

Source

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

6b) Please explain your ranking for organs and what the benefits/drawbacks of your preferred tool may be.

7. Are any specific organ-related activities that would be better regulated by a tool other than that which you have ranked first? (Please refer to 'processing' in glossary for list of activities.)

Ocular Tissue

8.a) Please rank the compliance monitoring and enforcement options according to appropriateness/effectiveness with respect to ocular tissue.

Source

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

Importers, Distributors

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

8.b) Please explain your ranking for ocular tissue and what the benefits/drawbacks of your preferred tool may be.

9. Are there any specific ocular tissue-related activities that would be better regulated by a tool other than that which you have ranked first? (Please refer to 'processing' in glossary for list of activities.)

Lymphohematopoietic Cells

10.a) Please rank the compliance monitoring and enforcement options according to appropriateness/effectiveness with respect to lymphohematopoietic cells.

Source

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

Importers, Distributors

• Registration
• Establishment Licensing (EL)
• EL Based on Health Canada Inspection
• EL Based on Third Party Inspection

10.b) Please explain your ranking for lymphohematopoietic cells and what the benefits/drawbacks of your preferred tool may be.

11. Are there any cell-related activities that would be better regulated by a tool other than that which you have ranked first? (Please refer to 'processing' in glossary for list of activities.)

Appendix A: Health Canada Considerations Regarding Specific Compliance Monitoring and Enforcement Tools

Strategy	Health Canada Considerations
1. Phase I Registration/ Declaration Scheme. This includes submission of an application for registration and an attestation to the Minister. Minister may request additional information to demonstrate that activities carried out in compliance with the Regulations.	Health Canada will know which establishments are involved in the handling of CTO. CTO establishments can start or continue operations with minimal delay. Is contrary to the Krever recommendation which was against voluntary compliance. Self attestation as a compliance mechanism may not be sufficient to minimize risk.
2. Establishment Licensing Based on Application This includes submission of information on key activities related to product safety. This information will be reviewed by Health Canada to assess the adequacy of processes employed by CTO establishments.	Health Canada will know which establishments are involved in the handling of CTO. Greater ability to detect and to manage risks before an adverse event occurs. Is consistent with the Krever recommendations. Is consistent with other compliance and enforcement tools used for other therapeutic products under the F&DA. Could utilize existing compliance/enforcement systems and resources.
3. Establishment License Based on Health Canada Inspections EL could be dependant upon an inspection by Health Canada inspectors. Inspections would involve requesting a sampling of the establishment's records, and descriptions of the processes or procedures. To assess compliance, it may also be necessary for the inspector to observe processes first hand.	Health Canada will know which establishments are involved in the handling of CTO. Greater ability to detect and to manage risks before an adverse event occurs. Highest level of control by federal government. Could utilize existing compliance/enforcement systems and resources. Is consistent with the Krever recommendations Is consistent with the treatment of other therapeutic products under the F&DA. Higher level of assurance by the regulator that the regulations are complied with.
4. Establishment License Based on Third Party Accreditation Health Canada could accept an accreditation from another organization as being equivalent to meeting the F&DA and CTO Regulations. Under such a scheme, accreditation by this external organization would be mandatory to obtaining an EL from Health Canada. A second possibility could be a designation-based scheme, under which Health Canada would authorize a third party to assess compliance with the F&DA and CTO Regulations. Health Canada could then have third party information submitted (i.e. reports from external inspectors, proof of an equivalent accreditation) and then make the ultimate decision regarding compliance.	Health Canada will know which establishments are involved in handling CTO. Greater utilization of more varied experience. Need to clarify responsibilities and accountabilities between Health Canada and third parties. Need to set up an accreditation system for CTO. May be costly for the CTO community depending on who bears the costs for such as system. Evaluation/assessment conducted by peers who are in the field. Hospital - based programs already familiar with accreditation.