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From: TSS (
Subject: BSE/CJD/TSE BLOOD WARNING LETTERS -- ZLB Bioplasma, Inc, and Belleza Integral C.A, and other warning letters update 9/24/04
Date: September 24, 2004 at 2:06 pm PST

-------- Original Message --------
Subject: BSE/CJD/TSE BLOOD WARNING LETTERS -- ZLB Bioplasma, Inc, and Belleza Integral C.A, and other warning letters update 9/24/04
Date: Fri, 24 Sep 2004 16:10:35 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

Public Health Service
Food and Drug Administration

Center for Biologics Evaluation
and Research
1401 Rockville Pike
Rockville MD 20852-1448

September 14, 2004




Craig B. Mendelsohn, M.D., J.D.
Medical Director
ZLB Bioplasma Inc.
801 N. Brand Blvd., Suite 1150
Glendale, CA 91203

Re: BLA STN #125070
Rhophylac® [RH0(D) Immune Globulin Intravenous (Human)]

Dear Dr. Mendelsohn:

The Food and Drug Administration's Center for Biologics Evaluation and
Research (CBER) has reviewed a sales brochure and a Patient Q&A for
Rhophylac® [Rh0(D) Immune Globulin Intravenous (Human)] (copies
enclosed) submitted by ZLB Bioplasma Inc. (ZLB) under cover of Form FDA
2253. We also reviewed a promotional web site maintained by or on behalf
of ZLB ( (excerpt enclosed). These
materials fail to reveal material facts regarding Rhophylac and,
therefore, misbrand the drug within the meaning of the Federal Food,
Drug, and Cosmetic Act (the Act). See 21 U.S.C. 352(a), 352(n), and 321(n).

Your failure to provide appropriate risk information misleads consumers
and professionals to believe that Rhophylac is safer than has been
demonstrated in the approved populations and encourages its unsafe use
in those for whom it is contraindicated.


Rhophylac is a sterile Rh0(D) Immune Globulin Intravenous (Human)
solution in a prefilled, ready to use syringe for either intravenous or
intramuscular injection. The FDA-approved professional labeling (PI)
states that Rhophylac is recommended for the suppression of Rh
isoimmunization in non-sensitized Rh0(D)-negative women, for Rhesus
prophylaxis in case of obstetric complications, for Rhesus prophylaxis
in case of invasive procedures during pregnancy, and for the suppression
of Rh isoimmunization in Rh0(D)-negative individuals transfused with
Rh0(D)-positive Red Blood Cells (RBCs) or blood components containing
Rh0(D)-positive RBCs.

Specific examples of risk information contained in the PI include, but
are not limited to, the following:

* A statement that "Rhophylac® is contraindicated in persons with
hypersensitivity to human globulin."
* The following warning: "Rhophylac® is made from human plasma.
Products made from human plasma may carry a risk of transmitting
infectious agents, e.g., viruses, and theoretically, the CJD
[Creutzfeldt-Jakob Disease] agent."
* The following precaution: "For postpartum use, Rhophylac® is
intended for maternal administration. It should not be given to
the newborn infant. The product is not intended for use in
Rh0(D)-positive individuals. Patients should be observed for at
least 20 minutes after administration."
The following Adverse Reactions: "Mild and transient fever,
malaise, headache, cutaneous reactions and chills occur
occasionally. In rare cases, nausea., vomiting, hypotension,
tachycardia, and allergic or anaphylactic type reactions,
including dyspnea and shock are reported, even when the patient
has shown no hypersensitivity to previous administration."

Failure to Reveal Material Facts

The main parts of your webpage, sales brochure, and patient Q&A make
claims of safety and effectiveness, but fail to provide risk
information, including the contraindications, warnings, precautions, and
adverse reaction information noted above (except that the webpage does
contain the warning regarding human plasma, and page 2 of the sales
brochure states that the product is "[p]repared from only US donor
plasma," but does not contain the whole warning). Although this
information appears in the PI accompanying the sales brochure and
patient Q&A, and is linked to the webpage, this is insufficient to make
the effectiveness claims appearing in the main parts of these items
non-misleading. The main parts of the Q&A and webpage include references
to the full prescribing information; however, this statement is not
sufficient to provide the appropriate qualification or pertinent
information for the effectiveness claims made in the main parts of these
items. Cf. 21 CFR 202.1(e)(3)(i). The webpage, sales brochure, and
patient Q&A fail to reveal material facts within the meaning of Section
201(n) of the Act and, therefore, are misleading and cause Rhophylac to
be misbranded under the Act. 21 U.S.C. 321(n), 352(a), 352(n).

Conclusion and Requested Action

The cited materials misbrand Rhophylac within the meaning of the Act
because they fail to reveal material facts regarding the risks
associated with the use of this product and are therefore, misleading.
21 U.S.C. 321(n), 352(a), 352(n).

We request that ZLB immediately cease the dissemination of promotional
materials for Rhophylac such as those described above. Please submit a
written response to this letter within ten (10) business days of the
date of this letter stating whether you intend to comply with this
request, listing all promotional materials for Rhophylac such as those
described above, and explaining your plan for discontinuing use of such
materials. Because the violation described above is serious, we request,
further, that your submission include a plan of action to disseminate
truthful, non-misleading, and complete information to the audience(s)
that received the violative promotional materials. Please direct your
response to me at the Food and Drug Administration, Center for Biologics
Evaluation and Research, Office of Compliance and Biologics Quality,
HFM-600, 1401 Rockville Pike, Rockville, Maryland 20852-1448, facsimile
at 301-827-3528. In all future correspondence regarding this matter,
please refer to the BLN/STN number and to CBER-04-016. We remind you
that only written communications are considered official responses.

The violations discussed in this letter do not necessarily constitute an
exhaustive list. It is your responsibility to ensure that your
promotional materials for Rhophylac comply with each applicable
requirement of the Act and FDA implementing regulations.

Failure to correct the violations discussed above may result in FDA
regulatory action, including seizure or injunction, without further notice.



James S. Cohen, J.D.
Acting Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and

A- Web Page
B- Sales Brochure
C- Patient Q&A

Public Health Service
Food and Drug Administration

Center for Biologics Evaluation
and Research
1401 Rockville Pike
Rockville MD 20852-1448



AUG 31, 2004

Belleza Integral C.A.
El Camoruco
Piso 12 Of 8
Av Bolivar N
Valencia, Venezuela 2001

To Whom It May Concern:

The Food and Drug Administration (FDA) has reviewed your website at
Internet address: and has determined that
several of the products on your website are being promoted for
conditions that cause the products to be drugs under section 201(g) of
the Federal Food, Drug, and Cosmetic Act (the Act) [21 USC 321(g)]
and/or biological products, as defined in section 351(i) of the Public
Health Service Act (PHS Act) [42 USC 262(i)].

Several of your Biocell Ultravital products, including H-Ultracell,
Cellorgane Complexe, Thymoenzym, Mekenz H7, and H-Citoplacell, are
considered drugs and/or biological products because the therapeutic
claims, as shown on your web site, establish their intended use as drugs.


H-Ultracell -- Your website states that H-Ultracell is an
"Anti-Ageing [sic] Vaccine" composed of ingredients including
"extracts of embrionary tissues of lamb foetus [sic]" " and "human
placenta." In addition, the website indicates that the product
includes "syringes with placental liquid of human origin." Your
website also states, "During the last 5 years, it has been proven
that H-Ultracell...improves cardiac performance and renal
function, as well as the functions of liver, spleen, and other
organs...; Reduces arterial tension, raises good cholesterol (HDL)
and reduces bad cholesterol (LDL);... Prevents osteoporosis...and
accelerates the recuperation from wounds...." Your website also
states, "No adverse reactions have been observed in any case in
the recommended doses" and "We recommend you to be "vaccinated"
every year...."


Cellorgane -- Your website states that Cellorgane is composed of
"biological components" including "organs and enzymes." Moreover,
"Cellorgane acts as a coadyuvant [sic] in specific treatments, and
it's afficiecy [sic] has been proof [sic] in the next cases:
Arterioschlerosis, ..., Arthritis, ...Immune system disorders,
Hepatic deficiency, Rickets." Your website also states that
Cellorgane has "no side effects" and that "tolerance,
antigenicity, and toxicity tests have determined that this product
is totally harmless in doses twice as large as those recommended
here" and is "Non-interactive with other medicines."


Thvmoenzvm -- Your website states that Thymoenzym is composed of
ingredients including "thymic extract which originates from young
calves" and that it is an "effective activator of the
immunological system...specially indicated to prevent and cure
bacterial and viral diseases." The website also indicates that
"Thymoenzyme is successfully used in: Hepatitis, Neuropathies,
Rheumatoid arthritis, Breast cancer, Kaposi's Sarcoma (AIDS),
Cancer of the Prostate, Lung cancer, Cancer of the Uterus,
Hodgkin's Disease."


Mekenz H7 -- Your website states that Mekenz H7 is composed of
ingredients including "cellular extracts of mesenchymatose
tissue." Moreover, the product is indicated for treating
"arthritis," "metabolic diseases," "neuromuscular diseases," and
"hypertension" among other things.


H-Citoplacell -- Your website states that H-Citoplacell is
composed of ingredients including "Human placenta" and "thymus
extract." Your website lists "Hypertension," "Degenerative
diseases," "Arterioschlerosis," and "Osteoporosis" as "some of the
ailments, deficiencies and chronic affections that substantially
improve with the continuous use of H-Citoplacell."

Regarding H-Ultracell, which your website indicates is composed of
ingredients including "fresh foetus [sic] tissue of unborn lamb," and
Thymoenzym, which your website indicates is composed of ingredients
including "thymic extract which originates from young calves," please be
advised that on December 12, 1997, the United States Department of
Agriculture (USDA) established restrictions on the importation of
certain ruminant products, including meat. and meat products from
ruminants, due to Bovine Spongiform Encephalopathy (BSE). The
regulations found in 9 CFR 95.4, specifically prohibit the importation
of ruminant products used in many of the commercial medias, extracts,
reagents, and anti sera, for in viva or in vitro use, Additionally, the
FDA has issued letters (dated May 3, 1991, December 17, 1993, May 9,
1996, and April 19, 2000) and a guidance document (September 1997)
requesting that manufacturers not use materials derived from ruminants
that have resided in or originated from countries where BSE has been
diagnosed in the manufacture of FDA-regulated products intended for
administration to humans.

It appears that Biocell Ultravital products, including H-Ultracell,
Cellorgane Complexe, Thymoenzym, Mekenz H7, and H-Citoplacell, are
offered for sale to U.S. citizens because the order page of your website
provides for payment and shipment to U.S. addresses. Furthermore, the
order page displays order numbers and a direct link to a U.S. Postal
Service website allowing individuals to track and confirm delivery of
products shipped into the U.S..

Please be advised that in order to introduce or deliver for introduction
a biologic into interstate commerce, a valid biologics license (BLA) or
new drug application (NDA) must be in effect. (21. U.S.C. 355(a); 42
U.S.C. 262(a)). A BLA or NDA is issued only after a showing of safety
and effectiveness (for an NDA) or safety, purity and potency (for a BLA)
for the product’s intended use. While in the development stage, drug and
biological products may be distributed for clinical use in humans only
if the sponsor has on file an accepted investigational new drug
application (21 U.S.C. 355(i); 21 CFR Part 312). Your product is not the
subject of an approved BLA or NDA or an IND. Therefore, your shipments
of product represent violations of the Act and/or the PHS Act and may
result in the Agency seeking such relief as provided by law. (21 U.S.C.

To avoid violating the Act and the PHS Act, you should immediately cease
distributing in the United States the products described above until you
receive an IND, BLA, or NDA from the FDA.

This letter is not intended to serve as an all-inclusive review of your
website and/or the products marketed by Belleza Integral C.A. It is your
responsibility to ensure that all products marketed on your website are
in compliance with the Act and the PHS Act and their implementing
regulations. You should take prompt action to correct the violations
noted above. Failure to correct these violations promptly may result in
regulatory action such as seizure without further notice.

Please notify this office in writing within 15 working days of receipt
of this letter of any steps you have taken or will take to correct the
noted violations and to prevent their recurrence. If corrective action
cannot be completed within 15 working days, state the reason for the
delay and the time within which the corrections will be completed. Your
response should be sent to James S. Cohen, J.D., Acting Director, Office
of Compliance and Biologics Quality, U.S. Food and Drug Administration,
Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville
Pike, Suite 200 N, Rockville, Maryland 20852-1448.

If you have any questions regarding this letter, please contact Ms. Anna
Flynn at (301) 827-6201.


James S. Cohen, J.D.

Acting Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

Source Plasma. Recall # B-1964-4.
Units 0141107409, 0141108210, 0141108897, and 0141109503.
ZLB Bioplasma, Inc., Tulsa, OK, by facsimile dated June 18, 2002. Firm
initiated recall is complete.
Blood products, collected from a donor who was at increased risk of
exposure to new variant Creutzfeldt Jakob Disease (nvCJD), were distributed.
4 units.


a) Cryoprecipitated AHF. Recall # B-2000-4;
b) Recovered Plasma. Recall # B-2001-4.
a) Unit 1794010;
b) Unit 4015236.
South Texas Blood & Tissue Center, San Antonio, TX, by facsimile dated
August 17, and September 25, 2001. Firm initiated recall is complete.
Blood products, collected from a donor who was at an increased risk for
variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
2 units.
TX, and FL.



a) Sheep Blood, Defibrinated ‚ Catalog Number 211946, Unit 100
ml. Recall # Z-1316-04;
b) Sheep Blood, Defibrinated ‚ Catalog Number 212391, Unit 250
Recall # Z-1317-04;
c) Sheep Blood, Defibrinated ‚ Catalog Number 212389, Unit 30
Recall # Z-1318-04;
d) Sheep Blood, Defibrinated ‚ Catalog Number 211947, Unit 500
Recall # Z-1319-04;
e) Sheep Blood, Defibrinated ‚ Catalog Number 211945, Unit 15
Recall # Z-1320-04;
f) Sheep Blood, Defibrinated ‚ Catalog Number 212390, Unit 100
ml. Recall # Z-1321-04;
g) BBL Brain Heart Infusion Agar w/10% Sheep Blood ‚ Catalog
Number 297655. Recall # Z-1322-04;
h) BBL TSA II w/5% Sheep Blood, Spacesaver ‚ Catalog Number
292537. Recall # Z-1323-04;
i) BBL Columbia C.N.A. Agar w/5% Sheep Blood/Levine EMB ‚
Catalog Number 295618. Recall # Z-1324-04;
j) BBL Brain Heart Infusion Agar CC w/ Sheep Blood ‚ Catalog
Number 296178. Recall # Z-1325-04;
k) BBL Columbia C.N.A. Agar w/5% Sheep Blood, ‚ Catalog Number
297831. Recall # Z-1326-04.
a) Lot number: 4155326 and Expiration date: June 29, 2004;
b) Lot number: 4155341 and Expiration date: June 29, 2004;
c) Lot number: 4155337 and Expiration date: June 29, 2004;
d) Lot number: 4155332 and Expiration date: June 29, 2004;
e) Lot number: 4155324 and Expiration date: June 29, 2004;
f) Lot number: 4155328 and Expiration date: June 29, 2004;
g) Lot number: 4146359 and Expiration date: August 02, 2004;
h) Lot number: 4153582 and Expiration date: September 09, 2004;
i) Lot number: 4153593 and Expiration date: August 26, 2004;
j) Lot number: 4153588 and Expiration date: September 23, 2004;
k) Lot number: 4154491 and Expiration date: August 19, 2004.
Becton Dickinson & Co., Sparks, MD, by facsimile on July 2, 2004. Firm
initiated recall is ongoing.
Sheep Blood products may be contaminated with a Brucella species (B. ovis).
Nationwide and Internationally.

> Sheep Blood products may be contaminated with a Brucella species (B.
> ovis).

WONDER what these products are used for and if they might contain
the scrapie/TSE agent?

a) Red Blood Cells Leukocytes Reduced. Recall # B-2019-4;
b) Fresh Frozen Plasma, Recall # B-2020-4.
a) and b) Unit 027LK13192.
American Red Cross Blood Services, Johnstown, PA, by telephone on April
1, 2004, and by letter dated April 1, 2004. Firm initiated recall is
Blood products, which were collected from a donor who was at risk for
Creutzfeldt-Jakob Disease (CJD), were distributed.
2 units.

a) Red Blood Cells Leukocytes Reduced. Recall # B-2021-4;
b) Recovered Plasma. Recall # B-2022-4.
a) and b) Unit 027LK12322.
American Red Cross Blood Services, Johnstown, PA, by telephone on April
4, 2004, or e-mail on April 8, 2004. Firm initiated recall is complete.
Blood products, which were collected from a donor who was at risk for
Creutzfeldt-Jakob Disease (CJD), were distributed.
2 units.
WV, and Switzerland.


FDA acts on pharma BSE risk


The government is taking steps to reduce the already minimal risk of
mad-cow tainted components ending up in childhood vaccines and other
medications, according to the Associated Press.

Pharmaceuticals regulated by the agency, including human vaccines and
animal drugs used on farms, routinely use cow products in their

The agency this summer strengthened safety measures to reduce the chance
of mad cow-tainted cow parts winding up in such consumer goods as
lipstick and hairspray.

William Egan, FDA acting director in the office of vaccine research and
review, told pharmaceutical representatives on Tuesday that the new rule
is aimed at reducing even further mad cow risk in human and animal
drugs. He did not offer specifics.

"It's under development. That's all I can say," Egan said during a
conference co-sponsored by PDA, an association of scientists involved in
drug development and manufacture.

There have been no reported cases of mad cow transmitted by medications.
Dozens of people, however, were infected with Creutzfeldt-Jakob disease,
related to the human form of mad cow, by taking tainted human growth
hormone between 1963 and 1985, according to the National Institutes of
Health. The method of manufacturing the growth hormone was changed in
response to that risk.

Eating beef from a diseased cow is thought to cause variant
Creutzfeldt-Jakob disease. More than 150 cases of variant CJD have been
reported in the world, primarily in Britain, and most of those people
have died. The one case of variant CJD in the United States was in a
young woman who likely contracted the disease while living in Britain.

In July 2000, the FDA told manufacturers to replace products in their
vaccines derived from cows born, raised and slaughtered in countries
with confirmed mad cow cases. Manufacturers hustled to find replacement
materials from countries whose cows were free of the always fatal brain

At the time, no North American cases of mad cow, formally known as
bovine spongiform encephalopathy, had been confirmed, until May 2003,
when a 6- to 8-year-old cow in Alberta, Canada tested positive for mad
cow. And, in December 2003, a second Canadian cow -- this one a 6
1/2-year-old imported into Washington state -- also was confirmed with
mad cow.

More aggressive surveillance by the Agriculture Department since June 1,
2004, has tested 63,341 American cow samples, said Lisa Ferguson, a USDA
senior staff veterinarian. Two samples initially were suspicious but,
upon further testing, were found not to contain mad cow.

The FDA's Egan said the agency has not yet decided whether manufacturers
will have to replace American and Canadian cow products routinely used
in vaccine manufacturing. Argentina, Australia, Iceland and Uruguay are
among the dwindling list of countries provisionally free of mad cow.

Also not clear is how the FDA would handle licensed vaccines currently
on the market or products progressing along lengthy development pipelines.

Even if American and Canadian sources of bovine-derived products were
prohibited, it's not clear how sweeping the impact might be.

One drug company, GlaxoSmithKline, already found alternate sources of
materials it uses to produce such products as hepatitis A vaccine and
recombinant hepatitis A and B vaccine. While Danielle Halstrom, a
GlaxoSmithKline spokeswoman, won't identify the source countries, she
said they do not include the United States or Canada.

"The entire process was completed more than a year ago ... to ensure we
only use materials from countries" with no mad cow infections, Halstrom

Cow remnants left over from slaughter have long been used to manufacture
drugs like vaccines. Serum is drawn from cow's blood and sugars from
cow's milk. Amino acids from cow bones are added to growth media to coax
along viral vaccines grown in living cells.

Egan suggested the companies consider plant-based and synthetic
compounds as substitutes, culturing methods that don't require serum,
and "closed" cattle herds known to be free of mad cow.

A Merck representative lobbied from the stage at Tuesday's conference,
urging the agency to first issue a letter with its intentions so
companies would have more time to prepare for changes that could affect
80 percent of pharmaceuticals.

"We have lifesaving medicines that we produce," said Taryn
Rogalski-Salter, a director in the company's department of global
regulatory policy, warning about potential supply disruptions.

Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a
Comment Number: EC -2
Accepted - Volume 7


the nutritional supplement industry as a whole, should be regulated the
same way that all pharmaceutical products are _suppose_ to be regulated.
and let us hope it is better than what they have done with the vaccine
industry and TSEs; TIP740203/l 0424 CONFIDENTIAL TWA LITTLE minute COMMERCIAL IN
prepared to believe in unofficial pituitary hormones, also in the
1970's, whether as described by Dr. Little, or in other circumstances,
for animal use. snip... The fact that there were jars of pituitaries (or
extract) around on shelves is attested by the still potent 1943
pituitaries, described in Stockell Hartree et al. (J/RF/17/291) which
had come from the lab. at Mill Hill. Having taken the trouble to collect
them, they were not lightly thrown out... more on the 1968
medicine act, they forgot to follow Draft cover
letter to product licence holders (considered by Human and Vet Medicines
including deer) (It was noted
with concern that hormone extracts could be manufactured by a veterinary
surgeon for administration to animals under his care without any
Medicines Act Control.) TWA LITTLE
STATEMENT 331 Nutritional
Supplements ======================= After 10 years of the same old
warning letter going out to the nutritional supplements industry about
sourcing there products from ''BSE free'' herds (no such thing,
especially in the USA), and the same flagrant ignoring of these facts by
the industry, the FDA MUST TAKE ACTION NOW! INGREDIENTS should be
accurately labeled, with _all_ ingredients. HEALTH CLAIMS should be
backed up with scientific data, backed up and verified by the same
Governing body that verifies pharmacueticals, and under the same
stringent safety regulations. ALL animal/human organs and tissues BANNED
in these products! INCLUDING From the Summer 2002, Venison & Velvet
newsletter of the elk and deer farming industry in Wisconsin. (In July
over 7,000 pounds of antlers were collected from state game farms for
pooled use in human nutritional supplements) from the State ''GAME
FARMS'' !!! CWD transmits to primates, cattle, mink, ferrits, sheep,
deer. CWD transmission studies have never been done on man. i am no
Doctor, i have no PhD, and am President of nothing. i make no money and
seek no monitary gains from my research. i simply seek the truth. ...


The large number of cases (1040), temporal clustering of the
outbreaks (15 in the first 6 months of 1997), the high in-flock
incidence, and the exceptional involvement of goats (390 cases),
suggested an accidental infection. The source of the
epidemic might have been TSE-contaminated meat and bonemeal, but
eight flocks had never been fed any commercial
feedstuff. Infection might have risen from the use of a formol-
inactivated vaccine against contagious agalactia prepared by a
single laboratory with brain and mammary gland homogenates of sheep
infected with Mycoplasma agalactiae. Although
clinical signs of TSE in the donor sheep have not been found, it
is possible that one or more of them were harbouring the
infectious agent. Between 1995 and 1996, this vaccine was given
subcutaneously to 15 of the affected flocks (to one flock in
1994); in these animals the disease appeared between 23 and 35
months after vaccination. No information is available for
herd 13 because it was made up of stolen animals. Sheep from the
remaining three flocks (1-3, figure) did not receive the
vaccine, thus suggesting a naturally occurring disease.


1: Dev Biol Stand 1996;88:237-41

Transmissible encephalopathies and biopharmaceutical production.

Robinson MM

USDA-ARS Animal Disease Research Unit, Washington State University,
Pullman, USA.

The use of post-mortem tissues as sources for the production of
biologicals, vaccines and feedstuffs has led to the transmission
or generation of transmissible encephalopathies in some recipients.
For example, the use of pituitary-derived human growth hormone and
gonadotropins has resulted in the transmission of Creutzfeldt-Jakob
disease to other humans [1], the use of formalin-inactivated sheep
brain as a source for louping ill vaccine led to the transmission of
scrapie to over 1,000 sheep from one vaccine lot [2], and the use
of rendered products from ruminant carcasses in the domestic animal
food chain led to the emergence and epizootic of bovine spongifrom
encephalopathy in the United Kingdom [3]. Infection with
transmissible encephalopathies by iatrogenic or other
mechanisms is difficult to
predict or control. The characteristics of these pathogens do not
permit easy detection, clearance, or inactivation in routine
biopharmaceutical production environments.

Publication Types:
Review, tutorial

PMID: 9119144, UI: 97169782

Louping-ill vaccine blunder to scrapie FULL TEXT

516 No 47. Vol. 58
November 23rd, 1946



The annual Congress, 1946, was held at the Royal Veterinary College,
Royal College Street, London, N.W.I. from September 22nd to September

Opening Meeting

[skip to scrapie vaccine issue...tss]

Blood donated after vaccination with rabies vaccine derived from
sheep brain cells might transmit CJD.

Arya SC.

BMJ 1996;313:1405 (30 November)
Blood donated after vaccination with rabies vaccine derived from sheep
brain cells might transmit CJD
EDITOR,--Janet Morgan reports that the National Blood Authority in
Britain has decided to tighten the donor screening programme to exclude
transmission of Creutzfeldt-Jakob disease or its variant through blood
donations.1 Prospective donors will be prevented from donating blood if
they have a history of treatment with human growth hormone or if one of
their siblings, parents, or grandparents developed the disease. I would
point out that similar care should also be taken when immigrants from
Asia and Africa offer to donate blood, in case they received rabies
vaccine derived from culture of sheep brain cells when they were living
in their country of origin.

In many countries in Asia and Africa limited supplies of imported rabies
vaccines derived from culture of human cells have been available. Many
people continue to be offered indigenously produced sheep brain vaccine
after exposure to a rabid animal. Scrapie is known to exist in sheep
around many centres where the vaccine is produced. In the mountain sheep
of the Kumaon foothills in the Himalayas, for example, scrapie was
established more than four decades ago and 1-10% of the flock was
reported to have the disease in 1961.2 In the Himalayan foothills the
Central Research Institute continues to produce four to five million
doses of sheep brain vaccine annually. Transmission of abnormal prion
protein, PrPsc, in sheep brain vaccine might have occurred in some of
the 30 documented cases of Creutzfeldt-Jakob disease in different
regions in India.3 Because Creutzfeldt-Jakob disease has a latency of
about 20 years, many recipients of sheep brain rabies vaccine could
emigrate to Britain before becoming ill.

Before accepting blood donations from immigrants it would be desirable
to ask the potential donors whether they were exposed to a rabid animal
and immunised with sheep brain rabies vaccine in their country of
origin. Furthermore, indirect assessment should be possible through, for
example, assay looking for antibodies specific to rabies.

Clinical microbiologist Centre for Logistical Research and Innovation,
M-122 (of part 2), Greater Kailash-II, New Delhi-110048, India

Subhash C Arya

: Neuroepidemiology 1991;10(1):27-32

Creutzfeldt-Jakob disease in India (1971-1990).

Satishchandra P, Shankar SK.

Department of Neurology, National Institute of Mental Health and
Neurosciences (NIMHANS), Bangalore, India.

Thirty cases including 20 definite and 10 probable cases of
Creutzfeldt-Jakob disease (CJD) seen in India between 1971 and 1990 are
reported. Demographic analysis has shown similarities to the previously
published reports from other parts of the world. Though 21 (70%) of
cases were from two centers--Bombay and Bangalore-, suggesting
clustering, this seems to be more apparent than real. One subject worked
in the medical field, where possibility of iatrogenic transmission could
not be ruled out. None of the cases had positive family history of CJD.
There is no epidemiological data of CJD from India so far and hence this
report is one such pilot study.

Furthermore, we showed that
the strain responsible for iCJD is closely related to that of one
patient with sCJD, and, more unexpectedly, that these agents were
similar to the French scrapie strain studied (but different from the
U.S. scrapie strain).

STUDY DESIGN AND METHODS: BSE was passaged through macaque monkeys and
then adapted to the prosimian microcebe (Microcebus murinus ). Brain
homogenate and buffy coat from an affected microcebe were separately
inoculated intracerebrally into three healthy microcebes (two animals
received brain and one received buffy coat).

RESULTS: All three inoculated microcebes became ill after incubation
periods of 16 to 18 months. Clinical, histopathologic, and
immunocytologic features were similar in each of the recipients.

CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months
earlier with BSE contained the infectious agent. This observation
represents the first documented transmission of BSE from the blood of an
experimentally infected primate, which in view of rodent buffy coat
infectivity precedents and the known host range of BSE is neither
unexpected nor cause for alarm.

TSE Advisory Committee 7/27/2000

I feel the need to say something. It's theoretical. I agree with your
sense of how often it's going to occur totally. What could we do? What
could they do?

This is Dixie Snider. Yeah, we can hear from him, but you made a
criticism of my comment, and I just want -- I thought it might be useful
to have something to go along with their U.S. Today story that they were
reading. That's all. Something that's authoritative from the FDA.

CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this

DR. RATZAN: If I could try to answer that, there is a scientific
nature to how do you look at communication. You don't overreact to
infinitesimal risks, and at the same time you don't under-react when
there is a real risk that's involved, because that does undermine the
public trust.

What I heard today were some of the steps that were being taken by some
of the manufacturers, the two that presented, that they are trying to
embody the public trust in terms of their processes. I think more of the
open nature, even meetings like this of being able to have advisory
meetings, meetings also that might have the professional associations
where you have opinion leaders who might be able to defuse the
information appropriately.

A blanket communication -- We often say Marshall McCluhan, a Canadian
scholar in media, said, if you try to reach everybody, you reach nobody.
By doing that, it's really key in thinking about communicating with the
people that need to know.

Ninety million Americans are either marginally or low literate, meaning
they can't understand a bus map or can't understand a bus schedule or
locate their intersection on a map. We can't communicate with the same
message to them that we might communicate to people who are making
vaccine decisions at the state or county or other levels.

So I'm answering in a circuitous way, because I think we've heard some
of the right steps being taken today, the open hearing, some of the
voluntary efforts that are being done in good faith by the
manufacturers, and some of the other ways that continue to monitor the
open disclosure. I think the surveillance systems that we've put in
place not only here in the United States but now abroad in looking at
BSE and looking at the CJD that we heard from CDC and others where the
numbers are.

So I would say, by all means, keep the surveillance. Keep the voluntary
efforts. Continue to focus upon the science, and communicate that
appropriately on, whether it's a quarterly basis, or use the different
channels, the Institute of Medicine channels that are out there.

I think there's a variety of different expert committees as well.
So, thank you.

CHAIRMAN BROWN: Thank you very much. Yes?

MS. FISHER: You may not want to communicate this theoretical risk to the
public, but that doesn't mean it's the right thing to do. I think that
part of what the National Childhood Injury Act of 1986 was all about,
the safety provisions, was communicating risk to parents before they get
their children vaccinated.

I think that, you know, the FDA's charge is to ensure the purity and
potency of vaccines. It seems to me that the least that we can do at
this juncture when we know something is to let the people know we know,
rather than keeping it from them.

CHAIRMAN BROWN: Hold on, Dave. Shirley?

MS. WALKER: There's an old German proverb, "Don't point the devil on
the wall; otherwise, he will jump off." I think the devil has already
jumped off.

The inserts in the packets for pharmaceuticals are great. Notification
to the doctor is great. But I represent something like 79,000 mothers
who have children in Dallas County who we actively promote to get

So Monday morning when I go back to work, I'm going to have to tell
someone, a percentage of these young mothers, that, hey, your child is
at risk for whatever that minute amount is for CJD. So what do we do at
this particular point? Do we remain mute and say nothing or do we
promote and give some type of information?

So I am saying to FDA that we do need some kind of general information
that we can impart to our constituents.

CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more
comments in this discussion, and then in the event that a number of
people on the committee may have to leave, there are two or three very
specific questions that the FDA would like some discussion-on, and I
want to move to them. We've touched on some of them already, but if
there's anything more to say on this -- Yes, go ahead.

263 DR. STEPHENS: I guess I'm really concerned that this discussion is
kind of spinning out of control in terms of the risk. I must agree with
the consumer advocate who spoke a minute ago --


DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a
duty, in my view, to protect the vaccine system in this country. I think
that this discussion has gotten to the point of at least suggesting that
we believe that this is a significant problem. The data suggests that
the risk is in the billions, that there have not -- there's not been a
single case of new variant CJD in this country,
despite the use of vaccines manufactured in this way for years.

So I think the issue is we need public disclosure. That's not the
question. I think we all are in agreement on this committee, but I think
to emphasize this point where you're concerned about going back to your
group of mothers and saying there's a risk -- I think that's something
we don't want to send. That's a message we do not want to send.

CHAIRMAN BROWN: I opened this whole seminar with the notion that we're
starting from a very, very small amount of infectivity, if there is
any, and that there is a tradeoff between, as several people have said,
a theoretical risk and a real risk, which would be discrediting in some
way vaccines or causing vaccine shortages or difficulties or refusal to
get vaccines.

In other words, this is the tradeoff. Right at the outset, this was the
scene that I hoped to set. But you're right. All of our committee
discussion meetings tend to spin out of control at about this time of
the afternoon, and sometimes it's in one direction, and sometimes
it's in another direction.

I think the word risk has enlarged as the afternoon has progressed, and
maybe we should shrink it down a little bit and get a little better
perspective or a little different perspective. So I tend to agree with
you. Let me --

DR. BOLTON: Paul, can I get in my comment?

CHAIRMAN BROWN: I'm sorry? Go ahead.

BOLTON: I agree that it would be important to communicate known risks or
even good estimates of risk to the public, but I'm not sure what
that estimate would be at this point. I don't think that we really have
enough information to communicate to the public and have it be
meaningful and not simply scare people away.

I can't imagine the negative impact on the program in this country if
parents started thinking that, if I vaccinate my child, he or she may
come down with new variant CJD.

To me, the other way that we communicate is by action. It seems to me
that there are actions that can be taken in terms of looking at the
process of vaccine manufacture and where the real -- the greatest of the
theoretical risks are. It seems to me that the viral/bacterial master
seeds are really at the very lowest end, as are the master cell banks,
and also trying to change those creates the biggest problem.

>From that point on, from the working seeds on down through production, I
think that the manufacturers have issues that they can address in terms
of removing the use of at-risk bovine materials from that point on.

I guess my question to anybody at the FDA is: Are at-risk bovine
materials currently in use at the -- certainly from the production step
on, and even at the production of the working seeds and working
cell lines, are they in use now, and how long before they will be phased

CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of
anything currently coming from BSE designated countries?

DR. STEPHENS: When I say at risk, I really mean those bovine materials
are coming from Europe or at-risk countries.

CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --

DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines
there was bovine derived fermentation media where that skeletal muscle
and pancreas derived from several European countries.
I think it was Germany, Denmark, Poland, the Netherlands.

CHAIRMAN BROWN: Right. So they are currently in use in this country.

DR. EGAN: They have all agreed to -- That will be changed, but as I
mentioned, by the time -- You know, they've gotten new sources, but that
comes into new vaccines -- What?

DR. BOLTON: Is that the only material that's now sourced from at-risk

DR. EGAN: That's used in the production. I think I also mentioned hemin.
I think that was it, but I'd have to go back to it.

DR. BOLTON: So I guess my recommendation would be that the FDA work with
the manufacturers to set a definite timeline to phase out all those
materials. In terms of the master virus seeds and the bacterial stocks
and the master cell lines, I think that the risk is so small as to be
really counterproductive to try to change those, because the risk of
changing the product by changing those is much, much greater than any
risk that there would be from proceeding.

CHAIRMAN BROWN: One of the questions that the FDA specifically wanted
some judgment on was: Is it necessary to re-derive bacterial master
seeds? I mean, I'm getting the sense -- Every time I get the sense of
something, the sense changes. You know, we had a consensus about
informed consent, and now we have a consensus about not smother it, but
be awfully, awfully, awfully careful.

Now I thought we had pretty much decided that, at least for current
products, that it will not be necessary to re-derive bacterial master
seeds. That was my sense. Dr. Huang?

DR. HUANG: I completely agree. I think that the derivation of new master
seed stocks would be more dangerous than this perceived danger that we
are facing now.

CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ
from that opinion? All right. We have answered one definitive question
that the FDA wanted to asked.

They also want an answer to a question I think should be very easy to
answer. That is: Is 1980, form all that you have heard, an appropriate
cutoff date before which one need not worry about anything in terms of
sourcing of the products we are talking about?

We always worry about something, but 1980 -- is that an appropriate date
before which not to be concerned? That's a pretty focused question. Is
there anybody that feels that one should be concerned
about products produced before 1980 from anywhere? Yes?

DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect
to our blood donation pool in the United States,'we were concerned about
BSE and started with 1980.

CHAIRMAN BROWN: It has the merit of consistency as well. All right.
That's two questions.

The third question they were concerned about was: Do we think that the
small amount of fetal calf serum from the U.K. around 1985 used in the
production of master cell banks constitutes a negligible or -- well, the
phrase was "a negligible or a significant risk"? Again, a question about
fetal calf serum, sourced from the U.K. in the middle of the
1980s, use in the production of master cell banks constitutes any kind
of significant risk? Yes?

DR. CLIVER: May I start by saying negligible. We'll see if anybody

CHAIRMAN BROWN: Do I hear significant? Negligible?

[[[sounds like a damn auction...tss]]]

DR. BOLTON: I agree that it's negligible.

CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used
for the production -- just for this specific purpose, used in the
production of master cell banks? Well, that answers the three questions
that you most wanted some judgment on Dr. Ewenstein?

Dr. EWENSTEIN: There was also the products that are still under
investigation. I think, you know, we should address that. I think one
of the comments before was, I think, right on the point. That is that
it's different if you have a licensed drug or product that
has, therefore, documented benefit versus recruited volunteers.

I think we should think about what we should answer for number 3. I
think that it's appropriate to include again, with the correct caveat,
about theoretical and negligibly small risk in a consent form. but I
certainly wouldn't like to see all clinical trials stopped of such

CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We
haven't touched on that, and we might just continue that discussion a
bit. Peter?

DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him
correctly. I think that it is indeed a different situation. For one
thing, not only is the benefit of the vaccine unknown, but for
another, one actually does know the name of the patients, and
one is personal contact with those patients on a semi-regular basis.

I think that the ethical responsibility toward those people is quite
different than is owed to the population at large......


DR. EGAN: As I mentioned in my opening
talk, for some bacterial vaccines there was bovine
derived fermentation media where that skeletal muscle
and pancreas derived from several European countries.
I think it was Germany, Denmark, Poland, the

CHAIRMAN BROWN: Right. So they are
currently in use in this country.

DR. EGAN: They have all agreed to -- That
will be changed, but as I mentioned, by the time --
YOU know, they've gotten new sources, but that comes
into new vaccines -- What+?

DR. BOLTON: IS that the only material
that's now sourced from at-risk countries?




The first is the FDA which threatened to
produce a regulation, but instead provided a guidance
which then provided them with no ability to enforce,
if it were necessary.
I think the lesson here is for all the
claims by some of the manufacturers who are here that
they are doing the best they can to get rid of the BSE
country sources for these vaccines, there are many
vaccine manufacturers who aren't here today.
So if we are to prevent this from
happening again, the first thing that needs to happen
is we need to regulate, not provide guidances; because
guidances can, and in this case were, ignored by the

The industry takes the other
responsibility for this. We have experts at the FDA
who came to the conclusion that the right approach to
this was to source the materials from non-BSE
countries, and the industary has recklessly, in my
view, decided simply to ignore that.
Had either of those two things been in
place, we wouldn't be here today, and all of this
discussion would have been unnecessary.


DR. BOLTON: And I guess that, I think,
emphasizes my point. That is that, in a real risk
situation, it even can taze years to take an action
versus here where we have a very less than negligible
theoretical risk. I don't think we should feel bad

about moving slowly, and I think it's inappropriate,
really, to talk about inappropriate actions on the
part of you, the FDA, or the vaccine manufacturers.
I think people are moving at an
appropriate speed and contemplating and thinking about
these issues very carefully.
CHAIRMAN BROWN: Thank you. I will ask if
anyone on either committee or the joint committee has
anything that they have not said that they definitely
want recorded as a public statement before I conclude
the day's proceedings.

I think the FDA was very astute not to ask
this committee to vote on any of the issues, but I
think the FDA has received a great deal of pros and
cons and discussion, and I think the meeting was very
worthwhile, and thank you all for coming.
(Whereupon, the foregoing matter went off
the record at 5:13 p.m.1

FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS

Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001
Date: Tue, 9 Jan 2001 16:49:00 -0800
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy BSE-L


[host Richard Barns]
and now a question from Terry S. Singeltary of
CJD Watch.

yes, thank you,
U.S. cattle, what kind of guarantee can you
give for serum or tissue donor herds?

[no answer, you could hear in the back ground,
mumbling and 'we can't. have him ask the question

[host Richard]
could you repeat the question?

U.S. cattle, what kind of guarantee can you
give for serum or tissue donor herds?

[not sure whom ask this]
what group are you with?

CJD Watch, my Mom died from hvCJD and we are
tracking CJD world-wide.

[not sure who is speaking]
could you please disconnect Mr. Singeltary

you are not going to answer my question?

[not sure whom speaking]



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