Conseils préparés par le groupe de travail de l'Union Européenne Cerezyme : Conseils à la Communauté "Gaucher" sur la Gestion d

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Guidance to the Gaucher Community on the Management of Cerezyme Supply

Temporary Conservation of Cerezyme Supply to Protect the Most Vulnerable Patients with Gaucher Disease

Guidance prepared by the EU Cerezyme Stakeholders Working Group, 24 June 2009
Jeremy Manuel
EGA Board Member

Yossi Cohen
EGA Board Member

Nadia Belmatoug, MD
Beaujon Hospital, Clichy, Ass.Publique-Hôpitaux de Paris, France

Maria Domenica Cappellini, MD
Milan University, Italy

Patrick Deegan, MD
Addenbrooke's Hospital, Cambridge, UK

Eugen Mengel, MD
Children’s Hospital, Gutenberg+University, Mainz, Germany

Anna Tylki-Szymanska, MD
Children’s Memorial Health Institute, Warsaw, Poland

Ashok Vellodi, MD
Great Ormond Street Hospital, London, UK

Ari Zimran, MD
Shaare Zedek Medical Center, Jerusalem, Israel

Susan Graham, MD
Global Medical Affairs, Gaucher disease, Genzyme Europe BV

Oved Amitay
VP, General Manager, Gaucher Disease Portfolio, Genzyme Corporation

Stephanie Hoffmann
Associate Director, Patient Group Relations, Genzyme Europe BV

Barbara Diana
Associate Product Manager, Genzyme Europe BV

*Please note that some individuals who participated in the Cerezyme Stakeholders Working Group are employees of Genzyme and other individuals or their institutions or organizations receive or have received funding from Genzyme for research, educational activities, and other purposes.

Background

Genzyme recently identified a virus (vesivirus 2117) in one of six bioreactors at its Allston manufacturing facility. This virus is not known to cause disease in humans, but it can impair the viability of the non-human CHO cells used to produce Cerezyme. Genzyme has temporarily suspended the production of Cerezyme® (imiglucerase) in order to sanitize this facility and to restore full production as quickly as possible. This manufacturing interruption will result in a temporary shortage in the supply of Cerezyme.

Additional lots of Cerezyme produced at the Allston facility have been tested for the presence of vesivirus 2117. No evidence of this virus has been detected. Based on this information, the FDA and EMEA authorized Genzyme to begin shipping the Cerezyme in inventory that had completed testing. Genzyme continues to work with the FDA and EMEA to test additional lots of Cerezyme that have not yet been released.

However, even with the release of this additional inventory, Genzyme still anticipates a supply shortage for Cerezyme. If no changes are made in the current patterns of Cerezyme use, the available supply is expected to “stock-out” at the end of July 2009 and the shortage would be expected to continue until mid-September or early October 2009 when additional Cerezyme becomes available following the restart of production (a stock-out period of approximately 6 – 8 weeks, based on current assumptions)

Gaucher disease is heterogeneous in its clinical manifestations and progression. A temporary interruption of Cerezyme treatment could have adverse health consequences for some of the most vulnerable patients. For this reason, a plan is needed to protect the most vulnerable patients by allowing them to continue treatment with Cerezyme at their current dosing regimen throughout the period of supply shortage.

In order to accomplish this objective, a Cerezyme Stakeholders Working Group was convened to develop and disseminate guidance recommendations to temporarily decrease the amount of Cerezyme used by the less vulnerable patients so that the conserved supply could be used to protect the most vulnerable patients until an adequate supply of Cerezyme is restored.

The Stakeholders Working Group includes a group of internationally-recognized physicians with deep clinical and scientific expertise in managing Gaucher disease. These physicians are not experts in virology and do not have an in depth knowledge of the manufacturing process of Cerezyme. The Stakeholders working group also included the European Gaucher Alliance (EGA) and representatives from Medical Affairs, Marketing and Patient Advocacy at Genzyme Europe BV (who provided background information and coordinated the meeting).

The Cerezyme Stakeholders Working Group embraced several principles in developing this guidance for temporary conservation of Cerezyme supply:
• The guidance should be designed to protect the most vulnerable patients.
• The guidance should be designed to minimize any risk for all other patients.
• The guidance should be the same irrespective of commercial or charitable access status.
• The guidance should be based on the best available evidence and experience.
• The guidance should aim for wide dissemination and compliance.
• The guidance should be simple to understand and practical to implement.
• Physicians should always make the final treatment decisions regarding their patient
Recommendations

The Cerezyme Stakeholders Working Group met via web conference on 24 June 2009 to address the following objectives:

1. Review and clarify, where appropriate, the EMEA recommendations to physicians concerning the management of the most vulnerable patients, whose Cerezyme treatment should not be interrupted
2. Review and clarify, where appropriate, the recommendations for temporary reductions in Cerezyme dosing or frequency of infusions for all other Gaucher patients
3. Discuss, refine and disseminate the EMEA recommendations for the Gaucher community on the management of Cerezyme supply during the period of temporary shortage

This guidance is based on the assumption that these recommendations should be applied only on a temporary, short-term basis, effective immediately, until the period of Cerezyme shortage ends.

EMEA DHCP Recommendations
Most vulnerable patients

a. Infants, children and adolescents should receive Cerezyme at the approved dose and infusion frequency, because these “early-onset patients” have the most rapid disease progression and are at risk of serious long-term problems

b. Adult patients with active disease progression (eg. pulmonary hypertension, active skeletal disease, severe thrombocytopenia or severe anaemia) should receive Cerezyme at the approved dose and infusion frequenc

Additional comments to the recommendations:
1. Pregnant women, type III patients, Gaucher patients with malignancy who are currently receiving Cerezyme should continue according to their current dose and frequency, without any interruptions

2. Gaucher patients who become pregnant and would benefit from treatment should be advised to consider commencing therapy

3. Newly diagnosed patients who meet the criteria for group (a) or (b) above, are recommended to initiate treatment with Cerezyme promptly.

Active skeletal disease is described as skeletal disease likely to benefit from treatment and ongoing symptoms, such as bone pain, ameliorated by treatment.

Physicians should always make the final treatment decisions regarding their patients on an individual basis.

EMEA DHCP Recommendations
Less vulnerable patients

a. Adult patients without clinical evidence of active disease progression should receive Cerezyme at a reduced dose (e.g. 50% dose once every two weeks) or at a reduced infusion frequency (e.g. once a month at their current dose).

b. No patient should be treated at a dose lower than 15 Units/kg every 2 weeks.

c. Active follow-up in this group should include monitoring of haemoglobin, platelets and chitotriosidase levels, as appropriate, at baseline and bimonthly.

Additional comments to the recommendations:

1. Stable adult patients who have been receiving Cerezyme treatment for ≥2 years could be considered for treatment interruptions for up to 3 months. During this period these patients should be monitored as deemed appropriate by the treating physician in partnership with the patient.

2. Dosing is frequently individualized and if deemed appropriate by the treating physician, doses below 15U/kg bi-weekly can be prescribed, if patients are already stable on these doses.

3. Newly diagnosed patients who do not meet the criteria for “most vulnerable patients” should defer initiating treatment with Cerezyme until the period of Cerezyme shortage has ended.

Any patient who has had a change in treatment regimen should be advised to seek advice from their treating physician should they suffer from Gaucher related symptoms (e.g. weakness, fatigue, abnormal bruising).

Physicians should always make the final treatment decisions regarding their patients on an individual basis.

General Guidance

a. The recommendations and guidelines should be implemented immediately and widely in order to conserve an adequate supply of Cerezyme for the most vulnerable patients.

b. The recommendations and guidelines should be implemented irrespective of commercial or charitable access status.

c. The recommendations and guidelines should be continued until notification by Genzyme that adequate supply has been restored.

d. At the end of this temporary period of Cerezyme shortage, it is recommended that all patients should resume their previously prescribed dosage regimen.

e. The recommendations may be subject to change if the guidance is not widely adopted or if Cerezyme production timelines need to be revised.

ICGG Gaucher Registry

Those physicians (and their patients) who are enrolled in the ICGG Gaucher Registry are encouraged to enter the clinical data collected during the shortage period and thereafter.

Adverse Events

Adverse events for Cerezyme should be reported to the pharmacovigillance department at Genzyme. Physicians are reminded to document batch numbers in the patient records.

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