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Factor Replacement Therapy

2.1 Introduction

The provision of safe, effective factor replacement therapy for the treatment of bleeding disorders* is based on these criteria:

1.    optimal quality
2.    optimal quantity
3.    universal accessibility
4.    home infusion
5.    effective recalls and recipient notification.

* “Bleeding disorders” are defined as all conditions, both congenital and acquired, characterized by a factor deficiency, including…
•    factor I deficiency (fibrinogen deficiency)
•    factor II deficiency (prothrombin deficiency)
•    factor V deficiency
•    factor VII deficiency (Alexander’s Disease)
•    factor VIII deficiency (hemophilia A)
•    factor IX deficiency (hemophilia B)
•    factor X deficiency (Stuart-Prower Deficiency)
•    factor XI deficiency (hemophilia C)
•    factor XIII deficiency
•    von Willebrand factor deficiency (von Willebrand Disease)
•    platelet function disorders.

The ultimate goal of effective factor replacement therapy for bleeding disorders is the provision of the safest, most effective products, as defined by the most advanced medical and technological knowledge, in optimal quantity, to enable people with bleeding disorders to lead full and productive lives. It is the mission of the Canadian Hemophilia Society to ensure that the products required to attain this high quality of treatment are provided within the context of comprehensive care universally accessible to all Canadians.

2.2 Optimal Quality

Factor replacement products should meet the criteria for optimal quality as defined by standards in three areas: safety, therapeutic value, and choice of product.

2.2.1 Safety

a)    Products must be free of all known disease-causing agents or contaminants.

b)    Products must demonstrate the lowest possible risk of transmitting unknown disease-causing agents or contaminants.

c)    While it is acknowledged that no blood product can be guaranteed to be completely safe, the Canadian blood system must strive to provide factor replacement products that are equal to or superior to the highest international standards.

d)    There must be a vein-to-vein tracking system for all factor replacement products which are derived from plasma, which contain plasma derivatives or which use plasma derivatives in their manufacturing.

e)    There must be an effective system for reporting and evaluating adverse reactions.

f)    An effective emergency response and notification system is required to ensure that all factor replacement products can be recalled within set time limits. (See 2.6, Effective Recalls and Recipient Notification.)

g)    The regulatory body, Health Canada, must have the necessary resources, both financial and human, to do effective post-marketing surveillance of approved factor replacement products.

h)    The Canadian Blood Services and Héma-Québec must have sufficient reserve funds to enable them to respond independently to any emergency situation without needing to obtain prior approval from Ministers of Health.

i)    All levels of safety (currently including donor screening, testing of individual donations for all known contaminants, plasma pool testing, purification, filtration, viral inactivation by approved methods and end-product testing) must be in place where appropriate.

j)    All plasma-derived factor replacement products must be treated with at least two proven effective viral inactivation processes (for example, nano-filtration, heat treatment or solvent detergent).

k)    Vaccination for those at risk for blood-borne viral infections must be provided, where appropriate.

l)    Treatment protocols must be developed for all types of factor replacement therapy to ensure that these valuable resources are being used in accordance with the most recent scientific knowledge.

2.2.2 Therapeutic Value

a)    Factor replacement products must create hemostasis (stop bleeding) within an appropriate time interval.

b)    Products must not lead to an increased risk of inhibitors.

c)    Products must not negatively affect immune function.

d)    Primary prophylaxis (regular infusions to prevent bleeding provided on a permanent basis) and secondary prophylaxis (regular infusions to prevent bleeding in a target joint provided on a temporary basis) must be provided where indicated.

e)    The elimination of animal and human proteins as stabilizers in the final formulation, or as nutrients in the cell culture, or in any other part of the process, should be considered as a goal in terms of the quality of recombinant products.

2.2.3 Choice of Product

Quality therapy implies that a patient and his/her physician have the option to choose products which meet that patient’s individual needs.    

a)    The decision as to choice of product should be made jointly by the physician and the patient (or his guardian).

b)    Access to a range of products to meet individual patient needs must be provided.

c)    Any long-term supply contracts or other long-term commitments of provincial funds must include penalty clauses for non-respect of contract provisions. They must also include provisions for opting to the supplier’s latest state-of-the-art factor replacement products.

2.2.4  Provision of Information on Clotting Factor Concentrates to Consumers

a)    As the patient or his/her immediate caregiver is ultimately autonomous in accepting or refusing any proposed treatment, the CHS believes that complete information on the risks, benefits and alternatives to clotting factor concentrates must be available. The primary source for such information is the prescribing physician; however, the CHS should also play a role in ensuring the appropriate distribution of accurate, balanced information on clotting factor concentrates. (See separate policy entitled, A Framework for Community Education and Interaction with Companies in the Pharmaceutical Industry.)

b)    The CHS will not reproduce in its own publications literature originally published by pharmaceutical companies but will exercise its own journalistic control.

c)    The promotion of factor concentrates, or other drugs, is acceptable only in defined circumstances, such as clearly-marked company kiosks at CHS information meetings or presentations within medical symposia. When such events occur, all pharmaceutical companies in the Canadian market must be invited. Information distributed must be approved under the provisions of the Pharmaceutical Advertising Advisory Board and/or the Health Protection Act.

d)    The CHS will not accept advertising of factor concentrates or other drugs in its publications. Brand names of factor concentrates or other drugs may be included in publications for information purposes. When this occurs, a disclaimer similar to the following will be included: “Brand names of treatment products are provided for information only. Their inclusion is not an endorsement of a particular product or company.”

2.2.5 Post-Marketing Surveillance

a)    In support of post-marketing surveillance for detection of blood-borne diseases, the Canadian Hemophilia Society endorses the Association of Hemophilia Clinic Directors of Canada’s Blood-Borne Pathogens Surveillance Project, located at the University of Alberta, encourages Hemophilia Treatment Centres to participate actively, and encourages patients to provide their informed consent to allow specimens to be collected.

b)    Inhibitor assays should be performed annually or when a lack of treatment efficacy is suspected.

c)    When patients switch brands of clotting factor concentrates, pre- and post-switch inhibitor essays must be performed to monitor for the development of this serious adverse reaction. Data must be collected and analyzed nationally.

2.3 Optimal Supply    

An optimal supply of factor replacement products is essential to ensuring the goal of quality therapy. There are three specific definitions of optimal supply.

a)    Products must be available in sufficient quantity to control bleeding following optimal care guidelines.

b)    Products must be available in sufficient quantity to meet all prophylactic needs.

c)    Products must be readily available to patients at the time they are needed.

2.4 Universal Accessibility    

a)    All factor replacement products used in the treatment of bleeding disorders (whether plasma-derived, recombinant or a future variant) must be considered as equivalent products for the purpose of coverage by Canada’s health care system.

b)    Gene therapy, when approved for use, must be considered as an equivalent to factor replacement therapy for the purpose of coverage by Canada’s health care system.

c)    Universal accessibility is a fundamental principle of a voluntary blood system and, as such, must be guarded as a 'sacred trust'. It is essential that all blood products and their substitutes, whether plasma-derived or bio-engineered, be available free of charge to all who need them.

d)    Prescribed prophylactic treatment for children and adults must be provided without additional cost.

e)    Recombinant factor replacement products must be available for those factor deficiencies for which they exist.

f)    Patients have a responsibility to be educated on effective and efficient utilization of factor replacement products.

g)    Education of physicians and patients as to the importance of cost accountability is recommended as a means to increase adherence to utilization guidelines.

2.5 Home Infusion    

Home infusion is the treatment mode of choice. The ability to treat oneself or a child in the home adds considerably to the efficacy of factor replacement therapy, to quality of life and has been demonstrated to dramatically decrease health care costs related to hospitalization and visits to Hemophilia Treatment Centres and out-patient clinics.

a)    Home infusion must be offered to those families whose frequency of treatment and ability to master safe technique have been demonstrated.

b)    Products must be packaged to allow for safe, convenient home use. Kits must be easily storable and transportable.

c)    Products must be labeled with appropriate information, warnings and instructions for use, written in easily understandable English and French.

d)    Products should have universal barcoding, radio-frequency identification or a future variant for inventory control and easy tracking.

e)    Products should be available in vials of different sizes to meet individual needs and avoid waste.

f)    Accurate documentation of utilization is needed to justify current utilization levels and to ensure availability to meet future needs.

i)    It is the responsibility of the person with a bleeding disorder, or his immediate care provider, to accurately provide treatment data — name of product, lot number, dose infused, date of infusion, site of bleed and adverse reactions — to his treating physician in a timely fashion.

ii)    No patient's health care should be detrimentally affected, particularly through product restriction, solely because the individual has elected not to participate in the collection of bleed sheet data.

iii)    Information on product use (the 'treatment log') which is currently maintained by each recipient of factor replacement therapy should be systematically collated to document current use.

iv)    The establishment of a clinic-based, confidential registry of product usage is supported.

v)    Future needs should be forecast to assure availability of appropriate products.

g)    The CHS supports the concept of electronic transmission of home care treatment data. Any system should have the following characteristics:
i.    nominal data should be sent directly to the Hemophilia Treatment Centre;

ii.    anonymous data can then be sent to the Canadian Hemophilia Assessment and Resource Management System (CHARMS) and on to third parties;

iii.    the system should be universal and accessible to all;

iv.    dial-up and transmission of information should be free of charge to the patient;

v.    patients will be entitled to a real copy in electronic format of all personal data uploaded to the Hemophilia Treatment Centre;

vi.    the system should be adaptable to new data entry technologies.

h)    The directors of recognized Hemophilia Treatment Centres must have the responsibility for tracking the distribution and the use of all factor replacement products in their respective territories, even when these products are distributed directly by the blood service or through another hospital. In addition, provincial governments must provide them the resources to do this.

2.6 Effective Recalls and Recipient Notification

2.6.1 General principles

a)    In the event of a recall, withdrawal or quarantine of blood or blood products, the Canadian blood system must be able to recover 100% of these products within a reasonable time, no matter whether these products are at distributors, in hospitals or in recipients' homes.

b)    In the event of a recall, withdrawal or quarantine of blood or blood products, the Canadian blood system must be able to notify 100% of those recipients who have already infused the products.

c)    All stakeholders in the Canadian blood system have a role to play in an effective recall-notification system:

•    the manufacturer to inform Health Canada and distributors in a timely manner, and to provide accurate information on the reasons for the recall as they become available;

•    Health Canada to oversee the recall / withdrawal / quarantine process, make decisions and ensure that all necessary measures are being taken in a timely manner;

•    CBS and Héma-Québec to notify all consignees (hospitals, blood banks, physicians, clinics, hemophilia treatment centres…) which products have been recalled, withdrawn or quarantined and why;

•    Ministries of Health to ensure the existence of information systems for accurate record-keeping, which permit the tracking of all transfusions of blood and blood products to the end-user, the patient;

•    hospitals, blood transfusion committees, blood banks, and ultimately physicians to notify their patients in the event of a recall / withdrawal / quarantine;

•    patient groups (e.g. CHS) to use their resources to educate their members about blood products and the recall / withdrawal / quarantine process.

2.6.2 Factor Replacement Products

a)    Directors of Hemophilia Treatment Centres in Canada, organized through the Association of Hemophilia Clinic Directors of Canada (AHCDC), must be mandated to track the use of clotting factor concentrates (factors I, II, VII, VIII, IX, X, XI, XIII and vWF). In the event of a recall / withdrawal / quarantine, they have the responsibility to notify patients registered in their respective clinics and recover the products.

b)    People with clotting factor deficiencies (factors I, II, V, VII, VIII, IX, X, XI, XIII and vWF) are encouraged to register at one of Canada's hemophilia treatment centres.

c)    Through an agreement among Ministries of Health, the CBS and Héma-Québec, and the AHCDC, physicians treating patients with clotting factor deficiencies who are not registered in one of the recognized Hemophilia Treatment Centres must send details regarding prescriptions (product, quantity, lot number, coded patient information) to a hemophilia treatment centre for purposes of notification in the event of a recall / withdrawal / quarantine.

d)    Where clotting factor concentrates are prescribed by a physician at a hemophilia treatment centre, but where the products are delivered by CBS/Héma-Québec or a third party, details (product, quantity, lot number, patient information) must be sent to that patient's Hemophilia Treatment Centre.

e)    The manufacturers, the distributors and, when necessary, Health Canada, must provide the Hemophilia Treatment Centres timely, accurate information on recalls, withdrawals and quarantines, including the reasons for them.

f)    Hemophilia Treatment Centres must be given the human and financial resources to properly track clotting factor concentrates and carry out notification procedures when necessary.

2.6.3 Voluntary Third Party Patient Notification System

a)    A voluntary third party Patient Notification System, which by its nature is unable to reach 100% of blood product recipients, must be seen, at best, as an interesting adjunct to a universal recall-notification system integral to Canada's blood system.

b)    The CHS believes that information available through the voluntary third party Patient Notification System on recalls / withdrawals / quarantines should be provided to the CHS, the AHCDC and the network of hemophilia treatment centres to supplement information from other parties.

c)    No recipient of blood products, specifically clotting factor concentrates, should have to rely on the voluntary third party Patient Notification System in order to be notified of a recall-withdrawal-quarantine.

d)    The decision to register in the voluntary third party Patient Notification System is entirely individual. A decision not to register must in no way affect an individual's right to receive timely notification of recall / withdrawals /quarantines from his/her physician.

e)    The creation of a voluntary third party Patient Notification System must in no way diminish the responsibility, or the ability, of the different stakeholders in Canada's blood system to implement an effective recall-notification process able to reach all consumers.

2.7 Gratuity of Other Hemostatic Agents

a)    Provincial governments must provide funds to Hemophilia Treatment Centres to ensure that the hemostatic agent desmopressin, in all its forms, and the anti-fibrinolytic, tranexamic acid, are made available at no cost to the patient when needed.

b)    Desmopressin in all its forms, and the anti-fibrinolytics, tranexamic acid, must be placed on all provincial formularies.

c)    Comprehensive and equivalent public pharma-care plans must be extended to all provinces.