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Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Red

Posted Jun 11 2012 6:17pm
Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products”
 
 
 
 
 
 
IN SHORT ;



“However, based on animal studies, as well as on FDA risk assessments, the possibility of vCJD transmission by a U.S.-licensed plasma derivative, while extremely small, cannot be absolutely ruled out. For these reasons, the recommendations for labeling for plasma derivatives will include mention of vCJD for the first time, and the potential risk for its transmission. The recommended elements of the warning label for CJD are unchanged and continue to describe its transmission as a theoretical risk, given that there is no confirmed evidence that CJD is transmitted by blood (Refs. 4-7).“




IN FULL, as follows ;






Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products”


DRAFT GUIDANCE


This guidance document is for comment purposes only.


Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.


Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or from the Internet at




or




For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail address listed above.


U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research June 2012


Contains Nonbinding Recommendations


Draft – Not for Implementation


Table of Contents


I. INTRODUCTION.............................................................................................................1


II. BACKGROUND...............................................................................................................2


III. RECOMMENDATIONS..................................................................................................3


IV. REFERENCES..................................................................................................................5


i Contains Nonbinding Recommendations


Draft – Not for Implementation


Guidance for Industry


Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products” This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.


I. INTRODUCTION


This draft guidance is intended to amend the guidance entitled “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products,” dated May 2010 (2010 CJD/vCJD guidance)(May 27, 2010),1 by revising the recommendations for labeling of plasma-derived products, including albumin and products containing plasma-derived albumin, to reflect current understanding of vCJD transmission through blood. When finalized, we will update the 2010 CJD/vCJD guidance by incorporating the revised labeling recommendations into the 2010 CJD/vCJD guidance, but will otherwise continue with our recommendations in the 2010 CJD/vCJD guidance as currently provided.


This guidance is intended for manufacturers of plasma-derived products, including albumin, and products containing plasma-derived albumin. Within this guidance, “you” refers to manufacturers and “we” refers to FDA. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.


1 This guidance is available at:




1


Contains Nonbinding Recommendations


Draft – Not for Implementation


II.


BACKGROUND


CJD and vCJD are two forms of transmissible spongiform encephalopathy (TSE) affecting humans.2 The Center for Biologics Evaluation and Research (CBER) first provided guidance for labeling of blood and blood products for CJD risk in November 1999, prior to reports of vCJD transmission by blood or plasma. We have continued to issue guidance on this topic as we continue to monitor epidemiological findings and other scientific data regarding CJD and vCJD. Since that time, four cases of presumed vCJD transmission by non-leukoreduced blood have occurred in the United Kingdom (U.K.). All of these were among recipients of blood from donors who later developed vCJD. In 2009, abnormal prion protein was discovered post mortem in the spleen tissue of a person with hemophilia3 with no symptoms of vCJD or other neurological condition. The patient, who was over 70 years old, died of other causes. This individual had received blood transfusions and large amounts of U.K. plasma-derived Factor VIII. A risk assessment performed by U.K. health authorities concluded that, assuming that the abnormal prion protein finding was a marker for asymptomatic vCJD infection, the most likely source of such an infection was plasma-derived Factor VIII, rather than dietary exposure, endoscopy procedures, or red blood cell transfusions.4


In the 2010 CJD/vCJD guidance, in section VII.B., we recommended revised labeling of blood and blood components for transfusion to address the possible risk of transmission of vCJD as a potential risk. At that time, we also said that FDA intends to further address labeling of plasma derived products, including plasma derived albumin and products containing plasma derived albumin, in future recommendations. We now recommend revisions to labeling for plasma derivatives, including albumin, and products containing plasma-derived albumin, to reflect current knowledge that vCJD has been transmitted by blood, and most likely by a plasma derivative.


At this time, plasma derivatives have not been implicated in vCJD transmission in any country other than the U.K. In the 2010 CJD/vCJD guidance, we recommended preventive blood donor deferrals for time spent in the U.K. and in Europe, and for other risks of Bovine Spongiform Encephalopathy or vCJD exposure. To date, no U.S.-licensed plasma derived products have been manufactured from a donor known to have developed vCJD and no cases of vCJD been reported from use of a U.S.-licensed plasma derivative. In addition, published studies and information submitted to FDA show that certain plasma derivative manufacturing steps can remove TSE infectivity, although such experiments have inherent limitations (Refs. 1-3). However, based on animal studies, as well as on FDA risk assessments, the possibility of vCJD transmission by a U.S.-licensed plasma derivative, while extremely small, cannot be absolutely ruled out. For these reasons, the recommendations for labeling for plasma derivatives will include mention of vCJD for the first time, and the potential risk for its transmission. The recommended elements of the warning label for CJD are unchanged and continue to describe its transmission as a theoretical risk, given that there is no confirmed evidence that CJD is transmitted by blood (Refs. 4-7).


Similarly, we are recommending revisions to the labeling for plasma-derived albumin and products containing plasma-derived albumin. In addition to its indications for direct infusion into patients, albumin may be used in the manufacture of other biological products. For example, it is used in the culture media of certain licensed vaccines or as a stabilizer in certain recombinant clotting factor products. Licensed albumin and albumin contained in other licensed products have never been known to transmit viruses, CJD or vCJD, and laboratory experimental evidence suggests albumin is less likely to contain CJD-like agents when compared with other fractionated products (Refs. 8-10). There is no epidemiological evidence for transmission of CJD or vCJD in the U.S., U.K., or elsewhere by products containing plasma-derived albumin. Therefore, our recommendations for revised warning statements for vCJD risk for plasma-derived albumin and products containing plasma-derived albumin contain additional language to reflect the extremely low likelihood of vCJD and CJD transmission through these products.


In October 2010, we sought the advice of the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) on our proposed labeling recommendations to reflect potential risk of vCJD in plasma-derived products. TSEAC agreed unanimously that labeling for the potential risk of vCJD is warranted for plasma derivatives, including albumin and products containing albumin (Ref. 11).


When finalized, the recommendations set forth below are intended to supersede the recommendations in FDA’s 2010 CJD/vCJD guidance at section VII.B (recommendations 2-4).


2 For the purposes of this document, FDA considers the less common TSEs, Gerstmann-Sträussler-Scheinker syndrome and fatal insomnia syndromes, to be equivalent in risk to familial and sporadic CJD.


3 Variant CJD and Plasma Products, Health Protection Agency (HPA), UK, http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733818681 .


4 vCJD Risk Assessment Calculations for a Patient with Multiple Routes of Exposure, HPA, Dept. of Health, UK, http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_100337.pdf .


2


Contains Nonbinding Recommendations


Draft – Not for Implementation




III. RECOMMENDATIONS


We recommend that you revise the statement in the Warnings and Precautions section of your labeling as follows:


Plasma-derived products Other than Albumin


“Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.” Plasma-derived Albumin


“Albumin is a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered


3


Contains Nonbinding Recommendations


Draft – Not for Implementation


extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin.”


Products Containing Plasma-derived Albumin


“This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.”


4


Contains Nonbinding Recommendations


Draft – Not for Implementation


5


IV.


REFERENCES


1. Foster PR. Removal of TSE agents from blood products. Vox Sanguinis. 2004. 87 (Suppl. 2): S7-10.


2. Lee, D.C., Stenland, J.C., et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy


infectivity during the purification of plasma proteins. Transfusion. 2001; 41: 449-55.


3. Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript, September 18-19, 2006, http://www.fda.gov/ohrms/dockets/ac/cber06.html# TransmissibleSpongiform.


4. Dorsey, K., Zou, S., et al. Lack of evidence of transfusion transmission of Creutzfeldt-Jakob disease in a US surveillance study. Transfusion. 2009; 49: 977-84.


5. Puopolo, M., Ladogana, A., et al. Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases. Transfusion. 2011; 51: 1556-66. 3004 1556.


6. Hewitt, P.E., Llewelyn, C.A., et al. Creutzfeldt–Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study. Vox Sanguinis. 2006; 91: 221–30.


7. Molesworth, A., Mackenzle, J., et al. Sporadic Creutzfeldt-Jakob disease and risk of blood transfusion in the United Kingdom. Transfusion. 2011; 51: 1872-73.


8. Brown, P., Cervenakova, L., et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion. 1999; 39: 1169-78.


9. Brown, P., Rohwer, R.G., et al. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion. 1998; 38: 810-16.


10. Gregori, L., Maring, J.A., et al. Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals. 2004; 32: 1-10.


11. Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript, October 28, 2010, http://











OR-36: A new neurological disease in primates inoculated with prion-infected blood or blood components


Emmanuel Comoy,1 Nina Jaffré,1 Jacqueline Mikol,1 Valérie Durand,1 Christelle Jas-Duval,2 Sophie Luccantoni-Freire,1 Evelyne Correia,1 Vincent Lebon,1 Justine Cheval,3 Isabelle Quadrio,4 Nathalie Lescoutra-Etchegaray,5 Nathalie Streichenberger,4 Stéphane Haïk,6 Chryslain Sumian,5 Armand Perret-Liaudet,4 Marc Eloit,7 Philippe Hantraye,1 Paul Brown,1 Jean-Philippe Deslys1 1Atomic Energy Commission ; Fontenay-aux-Roses, France ; 2Etablissement Français du Sang; Lille, France; 3Pathoquest; Paris, France; 4Hospices Civils de Lyon, Lyon, France; 5MacoPharma; Tourcoing, France; 6INSER M; Paris, France; 7Institut Pasteur; Paris, France


Background. Concerns about the blood-borne risk of prion infection have been confirmed by the occurrence in the UK of four transfusion-related infections of vCJD (variant Creutzfeldt- Jakob disease), and an apparently silent infection in an hemophiliac patient. Asymptomatic incubation periods in prion diseases can extend over decades in humans, and a typical disease may or may not supervene. We present here unexpected results of independent experiments to evaluate blood transmission risk in a validated non-human primate model of prion disease.


Methods. Cynomolgus macaques were inoculated with brain or blood specimens from vCJD infected humans and vCJD or BSE-infected monkeys. Neuropathological and biochemical findings were obtained using current methods used for human patients.


Findings. Thirteen out of 20 primates exposed to human or macaque blood-derived components or potentially contaminated human plasma-derived Factor VIII exhibited an original neurological disease (myelopathy) previously not described either in humans or primates, and which is devoid of the classical clinical and lesional features of prion disease (front leg paresis in the absence of central involvement, lesions concentrated in anterior horns of lower cervical cord, with no spongiosis or inflammation), while the 12 brain-inoculated donor animals and one transfused animal exhibited the classical vCJD pattern. No abnormal prion protein (PrPres) was detected by standard tests in use for human prion diagnosis, but higher amounts of protease-sensitive PrP were detected in cervical cords than in controls. No alternative cause has been found in an exhaustive search for metabolic, endocrine, toxic, nutritional, vascular and infectious etiologies, including a search for pathogen genotypes (‘deep sequencing’). Moreover, all the three animals transfused with blood treated with a prion removal filter remain asymptomatic with a one-third longer incubation period than the two animals transfused before filtration, which both developed the atypical syndrome presented here.


Interpretation. We describe a new neurological syndrome in monkeys exposed to various prion-infected inocula, including a potentially infected batch of plasma-derived Factor VIII. Our experimental observations in the absence of evident alternative etiology is highly suggestive of a prion origin for this myelopathy, that might be compared under some aspects to certain forms of human lower motor neuron diseases. Similar human infections, were they to occur, would not be identified as a prion disease by current diagnostic investigations.






Sunday, June 3, 2012


A new neurological disease in primates inoculated with prion-infected blood or blood components






disturbing to say the least.


I am seeing more and more atypical TSE disease that are NOT detectible with any standard TSE test today. the disturbing factor there would be, not knowing these cases exist, and the iatrogenic transmission there from via the medical, dental, surgical arenas. ...



Tuesday, May 29, 2012


Transmissible Proteins: Expanding the Prion Heresy






Wednesday, May 9, 2012


Detection of Prion Protein Particles in Blood Plasma of Scrapie Infected Sheep






Friday, May 11, 2012


ProMetic Life Sciences Inc.: P-Capt® Filtration Prevents Transmission of Endogenous Blood-Borne Infectivity in Primates





Wednesday, August 24, 2011


All Clinically-Relevant Blood Components Transmit Prion Disease following a Single Blood Transfusion: A Sheep Model of vCJD





Wednesday, August 24, 2011


There Is No Safe Dose of Prions





Sunday, May 1, 2011


W.H.O. T.S.E. PRION Blood products and related biologicals May 2011





Monday, February 7, 2011


FDA’s Currently-Recommended Policies to Reduce the Possible Risk of Transmission of CJD and vCJD by Blood and Blood Products 2011 ??





Sunday, August 01, 2010


Blood product, collected from a donors possibly at increased risk for vCJD only, was distributed USA JULY 2010





Tuesday, September 14, 2010


Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)





Sunday, July 20, 2008


Red Cross told to fix blood collection or face charges 15 years after warnings issued, few changes made to ensure safety





Saturday, December 08, 2007


Transfusion Transmission of Human Prion Diseases





Tuesday, October 09, 2007


nvCJD TSE BLOOD UPDATE





Saturday, December 08, 2007


Transfusion Transmission of Human Prion Diseases





Saturday, January 20, 2007


Fourth case of transfusion-associated vCJD infection in the United Kingdom





vCJD case study highlights blood transfusion risk 9 Dec 2006 by Terry S. Singeltary Sr.


THIS was like closing the barn door after the mad cows got loose. not only the red cross, but the FDA has failed the public in protecting them from the TSE aka mad cow agent. TSE agent ie bse, base, cwd, scrapie, tme, ...


vCJD case study highlights blood transfusion risk -












Saturday, May 26, 2012


Are USDA assurances on mad cow case 'gross oversimplification'?





in the url that follows, I have posted


SRM breaches first, as late as 2011.


then


MAD COW FEED BAN BREACHES AND TONNAGES OF MAD COW FEED IN COMMERCE up until 2007, when they ceased posting them.


then,


MAD COW SURVEILLANCE BREACHES.



Friday, May 18, 2012


Update from APHIS Regarding a Detection of Bovine Spongiform Encephalopathy (BSE) in the United States Friday May 18, 2012






Sunday, May 18, 2008



MAD COW DISEASE BSE CJD CHILDREN VACCINES









Saturday, January 16, 2010



Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al



Evidence For CJD/TSE Transmission Via Endoscopes



From Terry S. Singletary, Sr flounder@wt.net 1-24-3










TSS
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