22 septembre 2009
ACTELION, lettre du 08/09 relatif à la prescription de ZAVESCA suite à la pénurie de CEREZYME ( VESIVIRUS 2117)
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
ACTELION
AUGUST 2009
Dear Healthcare Professional:
In June 2009, Genzyme Corporation issued a press release announcing the detection of a virus in its recombinant cell cultures that produce the enzyme replacement therapy (ERT), imiglucerase. The contamination of cell cultures resulted in the immediate interruption of drug production and the subsequent supply shortage of Cerezyme® (imiglucerase) for some patients for a period of time. Since the announcement, Actelion has received direct requests from Healthcare Professionals for information regarding Zavesca® (miglustat) as an immediate option for patients who may not have access to imiglucerase treatment during the shortage.
Actelion would like to inform physicians that Zavesca® is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity or poor venous access). Zavesca® was approved and has been marketed in the United States since 2003. The decision to prescribe Zavesca® to patients is at the discretion of the treating physician. The physician should assess the risks and benefits of therapy for the individual patient.
Clinical studies where patients were switched from Cerezyme® to Zavesca® monotherapy have been conducted. One of these studies is described as follows:
The Study OGT 918-004 was a prospective, open-label, randomized clinical study over 24 months in which type 1 Gaucher patients were switched from ERT to Zavesca® monotherapy in one treatment arm. There were no significant differences for mean absolute changes in liver, spleen volume and hemoglobin concentration between the groups of patients switched to Zavesca® monotherapy and the Cerezyme® group. However, in adult type 1 Gaucher disease patients who had been treated with enzyme replacement therapy for at least 2 years, switching to Zavesca® as monotherapy was associated with decreases in platelet counts after discontinuation of enzyme replacement therapy. Platelet counts also declined after discontinuation of enzyme replacement therapy in patients originally randomized to combination therapy. [USPI; Elstein et al, Blood, 2007, 110(7):2296-2301] Important Safety Information for Zavesca®
§ Gastrointestinal disturbances (GI) such as diarrhea, flatulence and abdominal pain are the most common adverse side reactions associated with Zavesca® therapy.
— Diarrhea due to Zavesca® therapy usually responds to the introduction of a lactose-free and low carbohydrate diet and/or loperamide treatment.
§ Peripheral neuropathy has been reported in patients receiving Zavesca®.
— Patients should undergo neurological examination at the start of treatment and every 6 months thereafter; Zavesca® should be reassessed in patients who develop symptoms of peripheral neuropathy.
§ Zavesca® may cause fetal harm if administered to a pregnant woman.
— Pregnancy category X; Zavesca® is contraindicated in women who are or who may become pregnant; patients should be appraised of the potential hazard to a fetus.
§ There is a risk of impaired fertility in men.
— Men should maintain reliable contraceptive methods and not plan to conceive while taking Zavesca® and for 3 months after discontinuing treatment.
§ There is no experience with the use of Zavesca® in type 1 Gaucher disease patients under the age of 18 years.
Please consult the enclosed Zavesca® package insert for complete prescribing information. If you have additional questions or require additional information, please contact the Medical Information Department at usmedinfo@actelion.com or call toll-free (866) 228-3546 and follow the prompts for Medical Information.
Sincerely,
Kirk Taylor, MD Stefan Kolb, MD
Senior Vice President, US Medical Global Medical Leader, Zavesca®
Enclosure: Zavesca USPI 2008
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court | Suite 200 | South San Francisco, CA 94080 | phone +1 650 624 6900 | fax +1 650 589 1501 | www.actelion.com
© 2009 Actelion Pharmaceuticals US, Inc. All rights reserved. 09 319 01 00 0909
19 août 2009
Lettre de Genzyme du 3/08/09 aux US docteurs sur la gestion du stock et attente de la la FDA concernant la GENZ-112638
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Ghislaine SURREL
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Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
Tel 617-252-7500
August 3, 2009
RE: Revised Cerezyme® (imiglucerase for injection) Supply Management plan effective August 3, 2009
Dear Doctor:
As we previously informed you, we are in a period of temporary shortage of Cerezyme while we interrupt production to remediate a viral contamination of our manufacturing facility in Allston, Massachusetts.
Throughout this period, our overarching objective has been to protect the most vulnerable Gaucher patients.
On June 22, Genzyme convened a Cerezyme Stakeholders Working Group (including physicians and patient advocacy leaders) to develop a set of recommendations (a “Guidance”) for patient management designed to conserve supply for the most vulnerable patients. Across the U.S., physicians have begun to implement these recommendations. However, due to the complexities and time required to make these changes, we have not yet seen an adequate reduction in the usage of Cerezyme.
The projected levels of Cerezyme inventory are at a point where there is a high risk of not maintaining supply sufficient to protect the most vulnerable patients in August. The Cerezyme Stakeholders Working Group and FDA have been updated regarding this situation. As a result we have decided to begin more actively managing Cerezyme supply in order to preserve supply for the most vulnerable patients.
As of Monday August 3, 2009, Genzyme will implement a revised supply management plan which has been reviewed by the CSWG and which continues to have as its main objective conservation of Cerezyme supply for the most vulnerable patients.
The most vulnerable Gaucher patients will be defined as: infants, children and adolescents (≤18 years old) and patients with type 2 or 3 Gaucher disease. These patients should continue receiving Cerezyme according to their current dose and frequency, without any interruptions, and shipments will continue to these patients.
In addition, Genzyme will implement a Cerezyme Emergency Access Program (CEAP) which is designed to enable physicians to request Cerezyme for a limited number of other adult patients with life- threatening clinical situations defined as one or more of the following:
Platelet count ≤20,000/uL and/or documented bleeding diathesis Impending emergency non-elective surgery (e.g., splenectomy) Documented history of rapid and life-threatening disease progression following dose-reduction or treatment interruption.
Other life-threatening clinical situation which requires Cerezyme
The number of qualifying patients who will be able to receive Cerezyme through CEAP will depend on inventory levels. The CEAP form with instructions regarding the process is enclosed.
Other adult patients (>18 years old) will not receive shipments of Cerezyme as of August 3rd, in order to conserve supply for the most vulnerable patients defined above.
This revised supply management plan will be in effect through the month of August. At that point, the situation will be reassessed in consultation with the Cerezyme Stakeholders Working Group and the FDA, and we will inform the Gaucher community about any changes to the plan.
We anticipate having additional information to share with the community at that time regarding the availability of additional inventory of Cerezyme that is not currently approved for finishing and release by FDA. In addition, Genzyme has submitted a treatment IND for our investigational oral small molecule to treat Gaucher disease, GENZ-112638, and we anticipate a response from FDA regarding that treatment protocol by the end of August. In the meantime, if you need any further information, please contact Genzyme Medical Information (medinfo@genzyme.com or 800-745-4447, option 2). A copy of the Cerezyme US Prescribing Information is included with this letter.
We acknowledge that this has been a challenging period for the entire Gaucher community. As of today, the sanitization of the Allston facility has been completed, and the process of restarting production of Cerezyme has already begun. Throughout this time, thank you for working together with us to protect the most vulnerable patients until the supply of Cerezyme is fully restored.
Sincerely,
John Yee, MD, MPH
VP, Global Medical Affairs
Genzyme Corporation
Fabrazyme® (agalsidase beta) Update: Initial adoption of the Fabry Stakeholders Working Group Guidance appears to be strong, with many indications that physicians and patients have chosen to alter their treatment plans by missing a dose, reducing their dose, or changing the frequency of infusions. At this time, there is not a need to revise this Guidance. However, during this period of supply constraint, there continues to be a need for physicians to make the appropriate clinical decisions for each Fabry patient in consideration of the Fabry Stakeholders Working Group Guidance until the Fabrazyme supply is fully restored.
CZ-US-P067-08-09
14 août 2009
EMEA : Questions et réponses sur les stocks de Cerezyme et Fabrazyme
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Ghislaine SURREL
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European Medicines Agency
7 Westferry Circus, Canary Wharf, London E14 4HB, UK
Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16
E-mail: mail@emea.europa.eu http://www.emea.europa.eu
European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.
London, 14 August 2009
Doc. Ref. EMEA/510766/2009
Questions and answers on the shortages of Cerezyme and Fabrazyme
The European Medicines Agency has reviewed treatment recommendations from June 2009 on which patients should receive Cerezyme and Fabrazyme as a priority during the shortage of these two medicines over the next few months. The shortage, which is expected to last until the end of the year, is happening because of a problem in a factory where the active substances for the medicines are made.
The company has informed the Agency that the supply shortage of Cerezyme is more severe than it previously thought. Because of this, the Agency is now recommending the following:
• for Cerezyme, only patients at greatest need of treatment will receive Cerezyme but at a reduced dosage;
• for Fabrazyme, the recommendations given in June 2009 remain the same. They are ensuring that patients at greatest need of treatment continue to receive this medicine until the shortage is resolved.
What are Cerezyme and Fabrazyme?
Cerezyme and Fabrazyme are medicines that are used in two rare, inherited, life-threatening diseases in which patients have a lack of an enzyme involved in the breakdown of fatty substances in the body:
• Cerezyme is used in patients with Gaucher disease, a disease in which patients do not have enough of an enzyme called alglucerase. Cerezyme contains imiglucerase, which is a copy of the natural enzyme;
• Fabrazyme is used in patients with Fabry disease, a disease in which patients do not have enough of an enzyme called alpha-galactosidase A. Fabrazyme contains agalsidase beta, which is a copy of the natural enzyme.
In both medicines, the replacement enzyme is made by a method known as ‘recombinant DNA technology’: the enzymes are made by cells that have received genes (DNA) that makes them able to produce the enzymes. The cells are grown in special tanks called ‘bioreactors’ over a three- to four-month process, and the enzyme is extracted from the culture at regular intervals during the process.
Cerezyme has been authorised since November 1997 and Fabrazyme since August 2001. Both medicines are marketed in all Member States of the European Union.
What is the problem with Cerezyme and Fabrazyme?
Earlier this year, Genzyme, the company that makes Cerezyme and Fabrazyme, became aware of reduced yields from the bioreactors used to produce Cerezyme and Fabrazyme at their production site in Allston Landing in the United States of America. The company found out that the bioreactors were contaminated with a virus (a calicivirus of the type Vesivirus 2117). This virus is not known to cause disease in humans, but it can attack the cells used to produce these medicines. The contamination has an impact on cell growth, affecting the quantity, but not the quality, of the enzymes produced by the cells.
In June 2009, in order to sanitise the production facilities and conduct an investigation to prevent the contamination from re-occurring, the company had to stop the production of new batches of Cerezyme and Fabrazyme for an extended period of time. As a result of the supply shortage of both medicines, the company, in agreement with the Agency, recommended some temporary changes to the way Cerezyme and Fabrazyme were prescribed and used.
Although manufacturing is resuming, Genzyme has now informed the European Medicines Agency that the stocks of Cerezyme are lower than it said they were in June. Therefore the recommendations on the use of Cerezyme have had to be revised. These changes should be implemented immediately.
What are the recommendations while the shortages are ongoing?
Revised recommendations for Cerezyme
For Cerezyme, priority is given to infants, children and adolescents, and adults with severe, life- threatening disease progression:
• infants, children and adolescents should receive Cerezyme at a reduced dose or at a reduced infusion frequency. However, no patient should be treated at a dose lower than 15 units per kilogram body weight every two weeks, or alternative treatment should be considered.
• adult patients with severe, life-threatening disease progression should receive Cerezyme at a reduced dose or at a reduced infusion frequency. However, no patient should be treated at a dose lower than 15 U/kg every four weeks, or alternative treatment should be considered. In adult patients without severe, life-threatening disease progression, alternative treatment such as miglustat should be considered or treatment should be interrupted. Adults who demonstrate progression to severe, life-threatening disease should re-initiate treatment with Cerezyme.
Recommendations for Fabrazyme
For Fabrazyme, as in June 2009, priority is given to children and adolescents, and adult male patients, who should continue to receive Fabrazyme as one infusion every two weeks.
However, adult female patients, in whom the disease is less severe, may receive Fabrazyme at a reduced dose.
All patients will be closely monitored while treatment is suspended or while they are receiving reduced doses of Cerezyme or Fabrazyme. Reporting of side effects will continue as normal, with doctors recording the batch numbers of the medicines in each patient’s records.
These changes will need to continue until end of 2009 when the shortages are to be resolved.
What are the recommendations for prescribers?
• Doctors who look after patients with Gaucher or Fabry disease should be aware of the shortages, and should consider which patients should be switched to the reduced dose or other treatment.
What are the recommendations for patients with Gaucher disease who receive Cerezyme?
• Young patients with the disease (infants, children and adolescents) and adult patients with severe, life-threatening disease progression should be contacted by their doctor to discuss their treatment options. While the shortages are ongoing, they may be treated at a different frequency and with a reduced dose.
• Adult patients without severe, life-threatening disease progression should be contacted by their doctor to discuss the possibility of switching to alternative treatments (e.g. miglustat) or suspending treatment.
• Patients who have any questions should speak to their doctor or pharmacist.
What are the recommendations for patients with Fabry disease who receive Fabrazyme?
• There are no consequences for young patients with the disease (infants, children and adolescents) or for adult male patients.
• Adult female patients with Fabry disease should be contacted by their doctor to discuss their treatment options. While the shortages are ongoing, they may be treated at the same frequency (every two weeks) but with a reduced dose.
• Patients who have any questions should speak to their doctor or pharmacist.
What will happen next?
Genzyme is sending specific communications to all Cerezyme prescribers on how to select patients for dose reduction, switch to alternative treatment or suspension of treatment, according to the new recommendations. Genzyme has informed the Agency that no changes to the June recommendations are required for Fabrazyme.
Genzyme has also informed the Agency that these stock-sparing measures will have no impact on the supplies to ongoing clinical trials.
The European Medicines Agency will update this document as new information becomes available.
13 août 2009
Suiter au communiqué de Gezyme du 10/08/2009 : Distribution de Cerezyme®, nouvelles mesures temporaires de prescription
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Une information très récente (10/08/2009) du laboratoire Genzyme révèle que les stocks disponibles de Cerezyme® ont dû être sérieusement revus à la baisse, nécessitant en conséquence un réajustement des mesures de prescription temporaires.
Si le redémarrage des bioréacteurs du site de production d’Allston, aux Etats-Unis, a bien été effectué fin juillet, les premiers flacons de Cerezyme® à pouvoir être distribués ne pourront sortir qu’en décembre. Ce délai entre la remise en fonctionnement des bioréacteurs et la diffusion de sa production est normal dans un processus de culture de cellules.
Jusqu’à cette date, les règles de prescription de Cerezyme® ont du être réévalués selon les besoins des patients en cours de traitement et les stocks disponibles. C’est ainsi que le 25 juin dernier des mesures temporaires de prescription ont été communiquées par le laboratoire et l’EMEA.
Or, l’annonce du 10 août du laboratoire remet en question la mise à disposition d’une importante partie de ce stock disponible. En conséquence, de nouvelles directives de restriction pour la prescription de ce traitement vont devoir être très prochainement mises en oeuvre.
Pour vous faire connaître ces modifications, mais également pour étudier les autres possibilités thérapeutiques, Vaincre les Maladies Lysosomales en collaboration avec le Centre de référence des Maladies Lysosomales, coordonnée par le docteur Nadia BELMATOUG, vous invite à une réunion d’information le :
mardi 18 août 2009
à 14h00
à l’hôpital Beaujon
(centre de référence des maladies lysosomales)
L’entrée sera libre aux patients, nul besoin d’inscription. Si vous souhaitez plus d’informations, vous pouvez appeler VML ou le Centre de référence (01 40 87 52 86).
Coordonnées hôpital Beaujon : 100 boulevard du Général Leclerc – 92110 CLICHY
07 juillet 2009
Genzyme: Arrêt usine aux USA suite contamination par virus Vesivirus 2117 : problèmes approvisionnement Cerezyme,Fabrazyme
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Cerezyme et Fabrazyme : problèmes d’approvisionnement attendus
date: 06 juillet 2009
En prévision des problèmes d’approvisionnement attendus en Cerezyme (imiglucerase) et Fabrazyme (agalsidase bêta) durant les mois à venir, le Comité des médicaments à usage humain (CHMP) de l’Agence européenne des Médicaments (EMEA) recommande de délivrer prioritairement ces médicaments aux patients qui en ont le plus grand besoin.
Le Comité des médicaments à usage humain (CHMP) de l’Agence européenne des médicaments (EMEA) recommande de délivrer les médicaments Cerezyme (imiglucerase) et Fabrazyme (agalsidase bêta) aux patients qui en ont le plus grand besoin vu la rupture de stock attendue dans les mois à venir.
Le Cerezyme et le Fabrazyme sont des médicaments utilisés dans le cadre du traitement d’affections héréditaires rares liées à une déficience enzymatique. Le Cerezyme est administré aux patients souffrant de la maladie de Gaucher, une affection due à un déficit en alglucerase. Le Fabrazyme est administré aux patients souffrant de la maladie de Fabry, une affection due à undéficit en alfa-galactosidase A.
La rupture de stock prévue est une conséquence de la fermeture du site de production de Genzyme à Allston Landing (Etats-Unis), où ces deux médicaments sont produits. Après avoir détecté une contamination virale (calicivirus de type Vesivirus 2117), la firme a décidé de fermer son site de production pour pouvoir désinfecter les bioréacteurs. Le virus ne cause pas de maladies chez l’homme, mais il peut influer sur la quantité - pas sur la qualité - des enzymes produits dans les bioréacteurs. A l’heure actuelle, la firme essaie de déterminer l'origine de la contamination.
Le
Cerezyme et le Fabrazyme ne seront pas produits pendant la fermeture du
site de production. Tous les lots produits avant la détection de la
contamination ont été testés et approuvés par l’EMEA.
L’EMEA a approuvé certaines modifications temporaires proposées par la firme dans la manière de prescrire ces médicaments afin que les stocks existants puissent être utilisés le plus longtemps possible jusqu’à ce que de nouveaux lots puissent être produits. Ces modifications devraient être implémentées immédiatement.
Pour le Cerezyme, il est recommandé d’accorder la priorité aux nourrissons, aux enfants et aux adolescents, ainsi qu’aux adultes présentant des signes de progression active de la maladie. Ces patients devraient continuer à recevoir leur traitement d’après le schéma thérapeutique normal, c'est-à-dire une perfusion toutes les 2 semaines. Les patients adultes ne présentant pas de signes de progression active de la maladie devraient recevoir le Cerezyme à dose réduite (50 % de la dose une fois toutes les 2 semaines) ou à une fréquence réduite (dose actuelle 1 fois par mois).
- Pour le Fabrazyme, il est recommandé d’accorder la priorité aux enfants et aux adolescents, ainsi qu’aux adultes de sexe masculin. Ceux-ci devraient continuer à recevoir une perfusion toutes les 2 semaines. Les adultes de sexe féminin, pour lesquelles la maladie est moins grave, pourraient recevoir une dose moins élevée de Fabrazyme.
Il s’agit ici de recommandations temporaires qui ne changent en rien le Résumé des Caractéristiques du Produit (RCP) et la notice approuvés pour le Cerezyme et le Fabrazyme. Ces modifications de prescription seront sans doute nécessaires jusqu’à la fin de l’année.
Notes:
1. Des informations supplémentaires sont disponibles dans un document questions-réponses.
2. Des informations supplémentaires concernant le Cerezyme, p.ex. le RCP et la notice approuvés, sont disponibles dans le rapport européen public d'évaluation .
Des informations supplémentaires concernant le Fabrazyme, p.ex. le RCP et la notice approuvés, sont disponibles dans le rapport européen public d'évaluation.
3. Le présent communiqué de presse, ainsi que d’autres informations relatives au travail de l’EMEA, sont disponibles sur le site web de l’EMEA.
Contact : thierry.roisin@afmps.be
http://www.fagg-afmps.be/fr/news/news_cerezyme_fabrazyme.jsp?referer=tcm:291-62467-64
04 juillet 2009
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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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
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.
25 juin 2009
Comment la situation a été gérée (Vesivirus 2117)
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
How is the supply situation managed?
We recognize that access to treatment is a top concern for physicians, other health care providers, patients and their families during this temporary period of Cerezyme (Imiglucerase) and Fabrazyme (Agalsidase beta) supply constraints. It is our top priority as well. During this time period, we are committed to approaching access in a thoughtful, fair, and transparent manner according to these guiding principles for the allocation of the existing supply of Cerezyme and Fabrazyme:
Genzyme will work within the framework set by the regulatory authorities, to facilitate a consultation with expert clinicians and patient group leaders in order to implement the recommendations with the goal of preserving enough supply for the most vulnerable patients. To do this, the recommendations will ask a larger group of patients to conserve supply by missing or reducing doses for a temporary period, beginning as soon as possible.
The decision to conserve supply in this way ultimately lies with each individual patient and their physician. Genzyme cannot determine this treatment allocation on an individual basis.
Genzyme plans to manage the supply constraint during this period on a global basis – with all countries and regions contributing fairly, and without reference to commercial or charitable status.
We believe that working together as a community will help allow us to manage through this period of tight supply in the best way possible.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, the expected timing and duration of the Cerezyme and Fabrazyme supply constraint, and Genzyme’s plans regarding management of the supply constraint and its ability to preserve product for the most vulnerable patients. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; whether the needed number of patients and their physicians cooperate with the recommendations made in order to conserve supply and how quickly people begin conserving product; the receipt of regulatory consents, if and to the extent required, for the recommendations made to conserve supply; the accuracy of Genzyme’s product demand estimates; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/23/2009 at 02:38 PM | Permalink
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Informations sur l'approbation de la Cerezyme (Vesivirus 2117)
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Ghislaine SURREL
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06/19/2009
Information about FDA approval of some inventory of Cerezyme® (imiglucerase for injection) on Wednesday, June 17, 2009
We would like to share more information with you about the recent decision by the FDA to allow us to resume shipments of Cerezyme® (imiglucerase for injection) from our Allston facility.
On Tuesday, June 16, Genzyme explained in a conference call with the business community that some batches of Cerezyme at the Allston facility were being tested for the presence of Vesivirus 2117, using a technique called polymerase chain reaction (or PCR). No evidence of the virus was detected. We provided this information to the FDA on the morning of Wednesday, June 17. Based on their review of this information, the FDA subsequently authorized Genzyme to begin shipping these tested lots of Cerezyme in inventory that have completed testing. We continue to work with the FDA to test additional lots of Cerezyme inventory that have not yet been released.
However, even with the release of this inventory as a result of the authorization from the FDA, Genzyme still anticipates a supply constraint for Cerezyme starting during the August timeframe. We will carefully manage inventories of Cerezyme in conjunction with regulatory authorities, patient groups, physicians, and other health care providers, with the goal of protecting the most vulnerable patients.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, and the expected timing and duration of the Cerezyme and Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory being tested cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/19/2009 at 04:18 PM | Permalink
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Information sur la situation de Genzyme(Vesivirus 2117)
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Ghislaine SURREL
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Supply Update Facts
In response to your questions, we'd like to share the following information about Genzyme's supply situation. We will continue to share more information over time. Please refer back to this site or subscribe by email to receive future updates.
Genzyme has identified a virus in a single bioreactor used to manufacture Cerezyme at its Allston facility. This virus, Vesivirus 2117, is not known to cause disease in humans, but it impairs the viability of CHO cells.
We have tested some of the finished vials from affected lots of Cerezyme and the test was negative for Vesivirus 2117. The FDA has authorized us to begin shipping these tested lots of Cerezyme in inventory. We continue to work with the FDA to test additional lots of Cerezyme inventory that have not yet been released, and will provide more information as it becomes available.
Shipments of Fabrazyme are not on hold. This virus has not been detected in the production process for Fabrazyme.
Genzyme has temporarily suspended bulk production of Cerezyme and Fabrazyme in order to sanitize the Allston facility. We expect to restore full operations there in the latter half of July.
Current Cerezyme and Fabrazyme inventories are not sufficient to avoid shortages during this period of suspended production and recovery.
Genzyme continues to evaluate the impact of the interruption in production on the timing and magnitude of constraints on Cerezyme and Fabrazyme supply. The company currently expects the period of constraint for each product to last approximately 6-8 weeks. This period is expected to begin in August for Cerezyme and October for Fabrazyme.
We will carefully manage Cerezyme and Fabrazyme inventories in conjunction with regulatory authorities, patient groups, physicians, and other health care providers, with the goal of protecting the most vulnerable patients.
We believe that inventories will stabilize by the end of 2009.
Myozyme and Aldurazyme are not affected by the current situation.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, and the expected timing and duration of the Cerezyme and Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory being tested cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/19/2009 at 08:57 AM | Permalink
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23 juin 2009
FDA : (Vesivirus 2117) d'avertissement à Genzyme du 27/02/2009
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Ghislaine SURREL
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Genzyme Corporation 02/27/2009
Department of Health and Human Services Public Health Service
Food and Drug Administration
New England District
One Montvale Avenue
Stoneham, Massachusetts 02180
(781) 596-7700
FAX: (781) 596-7896
WARNING LETTER
NWE-08-09W
VIA FACSIMILE & CERTIFIED MAIL
February 27, 2009
Mr. Henri Termeer
Chairman, President and CEO
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
Mr. Termeer:
The Food and Drug Administration (FDA) conducted an inspection of Genzyme Allston Landing Facility, located at 500 Soldiers Field Road in Allston, MA, from September 15 – October 10, 2008. During the inspection the FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of licensed therapeutic drug products, bulk drug substances, and drug components. These products include Fabrazyme®, Cerezyme®, and Myozyme®. These deviations from CGMP include non-compliance with section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), the requirements of your biologics license application approved under 351 of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210 and 211.
At the close of the inspection the investigators issued a form FDA 483, Inspectional Observations, which describe a number of significant objectionable conditions relating to your firm’s compliance with CGMP. Significant deviations observed during the inspection include, but are not limited to, the following:
CGMP DEFICIENCIES CONCERNING DRUG PRODUCTS
1. Failure to establish and follow written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR § 211.113(b)]. For example:
a. Air flow pattern testing studies, executed in August of 2007 during the operational qualification of the HVAC system for fill suite FF2-16, do not fully demonstrate air flow movement away from work surfaces during representative personnel activities and manual simulations of the aseptic filling processes. For example the following operations and practices were not preformed during air flow pattern testing studies:
1. Critical aseptic connections
2. Routine functions of aseptic core operators, for example:
• Manually placing stoppers or reorienting stoppers using forceps for filled vials
• Withdrawing unfilled vials from the filling line for weight checks
• Redirecting filled vials typically with stoppers on the exit feed wheel
3. Unidirectional air flow over the rotary in-feed table
4. Opening the lyophilizer door or the automated double doors into the aseptic preparation area
5. Active viable air sampling
b. The aseptic filling of drug products on the (b)(4) filling line at the speed of (b)(4) has not been validated.
CGMP DEFICIENCIES CONCERNING BULK DRUG SUBSTANCES AND DRUG COMPONENTS
In addition, the inspection covered active pharmaceutical ingredients and significant deviations in the manufacture of your bulk drug substance and drug components were observed during the inspection. These deviations cause your bulk drug substances and drug components to be adulterated within the meaning of Section 501(a)(2)(B) of the FD&C Act. Specific areas of concern include, but are not limited to, the following:
Production and Process Controls
2. You failed to assure that there are written production and process controls designed to assure that the drug has the identity, strength, quality, and purity they purport or are represented to possess. For example:
a. Your firm does not conduct adequate monitoring of bioburden after hold times of intermediates or pooled buffers during purification of Fabrazyme®, Myozyme®, and Cerezyme®.
b. Pooled buffers used in purification steps are not adequately controlled for composition. Specifically, the current procedural and automated in-process controls for formulating pooled buffers do not assure that the pooled buffers will meet their specifications.
Your follow up to these documented deviations did not include training of operators or those supervising formulation operations.
Maintenance of Equipment
3. Written procedures are not followed for the maintenance of equipment used in the manufacture, processing, packaging or holding of drug substances. For example:
a. Internal surfaces and manual valves on the stainless steel chromatography columns used during drug substance purification are not adequately maintained. Maintenance has never been performed on the interior of columns to prevent adverse impact on cell cultures due to metal contamination. Visible rouging was observed on the exterior of the chromatography skid (b)(4) used in purification of Myozyme®.
b. For the Cryoshippers which are used to transport master cell banks and working cell banks between manufacturing facilities: (1) The use of these cryoshippers has not been validated, (2) Maintenance has not been performed on any of the (b)(4) shippers in use at the time of the inspection, and (3) The manual for these shippers states that the life expectancy of the shippers is 5 years. (b)(4) of these shippers have been in use since approximately late 2002 or early 2003.
Computerized Systems
4. Your firm failed to maintain computerized systems in a validated state. For example, the (b)(4) console, used for formulation for the elution buffer for Fabrazyme®, has not been updated since 1999. The specific gravity value entered into this system in 1999 is incorrect.
The deficiencies described in this letter are indicative of your quality control unit’s failure to fulfill its responsibility to assure the identity, strength, quality, and purity of your drug products and drug substances.
Genzyme’s written responses dated October 31, 2008, and February 23, 2009
We have reviewed your written responses dated October 31, 2008, and February 23, 2009, addressing Form FDA 483 issued October 10, 2008, and acknowledge your report of completed and in-progress corrective and preventive actions. Additional details to fully evaluate the adequacy of the corrective actions are needed. Our evaluation of your responses and request for further information follows, and is numbered to correspond to the items listed on the Form FDA 483:
Observation 1
Please provide the protocol(s) for your engineering studies and procedures for your new bioburden monitoring program. Regarding your procedures for collecting data to establish bioburden action limits for purification intermediates and drug substance, please address
• whether the (b)(4)referenced in your October 31, 2008 response are from different (b)(4) production lots.
• the basis for any sampling performed.
• the basis upon which appropriate action limits will be established, particularly with regard to infrequently manufactured products.
Please provide an update on the bioburden monitoring programs described in your responses.
Also, please explain your procedures for tracking the length of time that intermediates, drug substance, and buffers have been held.
Observation 2
Please provide the protocol(s) or procedure(s) for collecting data to establish bioburden action limits for pooled buffers. Also, please address
• whether the (b)(4) referenced in your October 31, 2008 response are from (b)(4) different production lots.
• the basis for any sampling performed.
• the basis upon which appropriate action limits will be established, particularly with regard to infrequently manufactured products.
Please provide an update on the bioburden monitoring programs described in your responses.
Please provide an update on the initial evaluation of buffer composition and provide the protocol(s) for the follow up studies referred to in your February 23, 2009 response.
Please provide a summary of the “technical evaluation of the in-process controls tests used to confirm buffer formulation” to which you committed to conduct in your October 31, 2008 written response.
Please address re-training of the operators formulating buffers and those supervising these operations. Our inspection noted that your firm documented deviations in the formulation of pooled buffers, but failed to conduct re-training as follow-up to the deviations to prevent their recurrence.
Observation 6
Your February 23, 2009 response indicates that you have completed your proposed corrective actions with respect to Observation 6, which included an additional air flow pattern study to qualify the HVAC system for fill suite FF2-16. Please indicate if your firm continued aseptic filling operations in fill suite FF2-16 prior to completing this air flow pattern study. If you continued filling operations please provide your justification and evaluation of product impact. In addition, please provide the final report from the air flow pattern study.
Observation 4B, 7, & 11
Your October 31, 2008 response indicates your firm continues to operate the (b)(4) aseptic fill line at speeds up to (b)(4) prior to validating the operation. Please provide your justification and evaluation of product impact.
Please clarify when your firm intends to validate the aseptic filling line. In response to FDA 483 Observation 7, you committed to execute validation of the fill line speed in December 2008. However, in response to FDA 483 Observation 11, you committed to validating the fill line speed in the third quarter of 2009. It is not clear when you will validate the aseptic fill line. Please provide specific details and documentation of your proposed action.
Observation 9
Please indicate if the chromatography column in question remains in use, if it has been evaluated or if maintenance has been performed. If the column is or will remain in use, please provide your justification, including evaluation of the column and any maintenance performed, and an evaluation of product impact.
Observation 10
We acknowledge your commitment not to use the cryoshippers prior to execution of validation for transport of cell banks between the Framingham, MA and Allston, MA facilities. However, these cryoshippers are also used to transfer cell banks from Framingham, MA to San Diego, CA and to Belgium. Please indicate whether you have also ceased using the cryoshippers for cell bank shipments to San Diego, CA, and Belgium until the validation is completed. If not, please provide a justification.
Observation 15
We acknowledge your commitment to identify inconsistencies between the (b)(4) automated system and the production records regarding specific gravity values for buffers your firm manufactures (e.g. Fabrazyme Elution Buffer).
The inspection team noted that this automated system, containing formulas and recipes for buffers was programmed in 1999 and has not been reviewed or updated. We are concerned that other discrepancies in other values may exist. Please comment on how you will assure all values programmed (b)(4) into the automated system, and other automated systems, are consistent with current master batch records.
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the FD&C Act, PHS Act, all applicable federal laws and regulations, and the standards in your license. Federal agencies are advised of the issuance of all Warning Letters about biological products so that they may take this information into account when considering the award of contracts.
Please notify this office in writing, within 15 working days of the receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence .Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in further regulatory action without further notice. Such actions may include license suspension and/or revocation, seizure or injunction.
Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug application listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary.
If you no longer manufacture or market any of your drug products, your response should so indicate, including the reasons for, and the date on which, you ceased production.
Please direct your response or any questions you may have to Amber Wardwell, Compliance officer, Food and Drug Administration. One Montvale Avenue 4th Floor, Stoneham, Massachusetts 02180. Her telephone is (781) 596-596-7823.
Sincerely yours,
/S/
John R. Marzilli
District Director
New England District
