Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and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”
Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and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Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance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DRAFT GUIDANCE
This guidance document is for comment purposes only.
Submit one set of either electronic or written comments on this draft
guidance by the date provided in the Federal Register notice announcing the
availability of the draft guidance.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
http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/all-clinically-relevant-blood.html
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
posted by Terry S. Singeltary Sr. at
5:17 PM
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