PRELIMINARY SUMMARY

TSEAC MEETING

October 25 & 26, 2001

(revised 11/2/01)

TOPIC 1. FDA's Draft Guidance on Revised Preventive Measures to Reduce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
(published in the Federal Register on August 29, 2001

Dr. Dorothy Scott, Medical Reviewer, OBRR, FDA, presented a summary of
the previous committee discussion on donor deferral issues from the June
28 & 29 TSEAC meeting. She then gave an overview of FDA's draft
guidance, focusing upon the new donor deferrals for risk of vCJD, as
recommended by the TSEAC on June 28, 2001. Dr. Scott briefly reviewed
the rationale for not deferring donors who lived in the U.K. since 1996,
which is based upon effective measures to prevent entry of BSE into the
human food chain. She mentioned the recent finding of BSE in Japan,
which is under discussion at FDA. In addition, she reviewed the
rationale for deferring blood, but not Source plasma donors who have
lived in Europe, for vCJD exposure risk. This draft recommendation is
based upon scientific studies, which suggest that plasma derivative
manufacturing removes TSE agents, and upon concerns about the impact of
such a deferral upon availability of products such as IGIV and Factor
VIII. Finally, she reviewed efforts which are being made, within the
guidance, and without, to attenuate the impact of new deferrals on the
blood supply. A more comprehensive review of this issue by the TSEAC is
anticipated in the near future. The draft guidance will be open for
public comment until October 28, 2001.

Next the Committee received a report from Dr. Stephen Nightingale,
(Executive Secretary DHHS Advisory Committee on Blood Safety and
Availability) on DHHS 's recent monitoring program for blood supply and
current plans to extend this monitoring program to the supply of plasma
derivatives and their recombinant analogs. He then gave a summary of the
DHHS meeting held on September 24, 2001 to discuss the Department's
BSE/TSE Action plan (draft summary on web site). The committee then
heard presentations from America's Blood Centers, American Red Cross,
New York Blood Center and the Department of Defense. As a result of the
open public hearing and these presentations the committee received
suggestions for improving the DHHS monitoring program, and suggestions
for FDA's consideration on their Draft Guidance. The committee chair
stated that it would be nice to have a uniform set of blood donor
deferral criteria, but that two sets of criteria can exist and that the
two sets of criteria may eventually evolve and the differences may be
reduced.

## 

TOPIC 2. Discussion of Amino Acid Sourcing and Production, and the
Theoretical Risk of Transmission of the BSE Agent Through Their Use in
Biopharmaceutical Products

The committee heard presentations from major amino acid manufacturers on
their current and previous sourcing of amino acids and their production
processes.

The committee's discussion focused on reducing risk of TSE transmission
as a result of the use of amino acids as reagents or excipients in other
CBER regulated compounds. They discussed the possibility of requiring
manufacturers to validate their process if they choose to use bovine
derived material (with the exception of milk and hair). They suggested
that although the risk of TSE transmission was low, that manufactures
should avoid using bovine material and if used, it should be sourced
from a BSE-free country. However, they acknowledged that the designation
of BSE free countries was difficult and constantly changing and in most
cases the manufacturers had already switched from bovine to vegetable
sources. They emphasized that due to the amino acid production processes
which included hydrolysis, purification, chromatography and filtration
that the risk of TSE transmission was very small.

It should be noted that the committee stated that the potential risk
posed by amino acids for production of products already on the market is
so minimal that no effort need be made in constraining use or
availability of these products.

The committee then voted on the following three questions.

# Questions

1.  Does the committee think that the current manufacturing process and
    control methods utilized by the manufacturers of amino acids can
    minimize the risk to allow bovine-derived amino acids from BSE
    countries to be used as reagents and excipients for the production
    of pharmaceutical products?

> **The committee voted: 1 yes vote, 18 no votes, and 0 abstentions.**
>
> The committee then voted on a recommendation formulated by the chair:
>
> That the committee should recommend to FDA not to allow ruminant
> source material (with the exception of material such as milk and hair)
> to be used from BSE countries.
>
> **The committee voted: 18 yes votes, 1 no vote (one member changed his
> vote to this "no" vote after the initial count, but before the meeting
> adjourned) and 0 abstentions.**

2.  The committee modified this question to - Does the committee think
    that in all circumstances the risk:benefit ratio would still be in
    favor of a subject receiving any product where suspect amino acids
    had been used during manufacture of that product?

> **The committee voted: 19 yes votes, 0 no votes, and 1 abstention**.

3.  If not, does the committee think that the current manufacturing
    process and control methods utilized by the manufacturers of amino
    acids can minimize the risk to allow other ruminant-derived amino
    acids from BSE countries to be used as reagents and excipients for
    the production of pharmaceutical products?

Based on the other answers this question is now a "moot point".

4.  Question 4 in the briefing packet was not discussed.

## 

TOPIC 3: Bovine Brain, Spinal Cord, and Other Neurological Tissue in
Foods, Drugs, and Cosmetics for Human Use

The Committee received an over view and background information from Dr.
Robert Brackett of CFSAN, followed by a presentation on "Opportunities
to Prevent Contamination of Edible Products in a Slaughter Plant with
the BSE Agent" from Dr. William James of the Food Safety Inspection
Service, USDA. Dr. James particularly described procedures in
slaughtering (e.g., stunning, splitting heads and carcasses) and in
mechanical recovery of meat from bones that may, if not performed
properly, result in contamination of muscle meat with CNS tissue. There
was discussion also of the wide variety of products that bovine CNS and
recovered meat may be used in, often without labeling to inform the
consumer.

##### Questions

The committee modified the FDA presented questions to read:

1A. Is there a public health risk to consumers that would warrant
consideration of prohibiting the sale of bovine brain for human use?

**The committee stated that the presence of undiagnosed or pre-clinical
BSE should be considered a health risk. Risks can also be due to
products coming from countries that were considered to be BSE free which
later detected the existence of BSE. And the risk to the consumer of
un-knowingly purchasing products that contain brain and CNS tissue
should also be considered**

**The committee voted: 17 yes votes, 1 no votes, and 0 abstentions**.

1B. Is there a public health risk to consumers that would warrant
consideration of prohibiting the sale of products containing brain for
human use?

**The committee voted: 18 yes votes, 0 no votes, and 0 abstentions**

2\. Is there a consistent and appreciable difference in infectivity of
various sections/areas of bovine brain? If so, what are the differences
in relative degrees of infectivity of these areas?

**There are differences in infectivity in different areas of the brain,
but those differences are not reproducible and therefore should not be
used to rank the relative risk of using various sections of a
BSE-infected brain. The committee requested information on the current
state of surveillance and Dr. Lisa Ferguson gave a short presentation on
USDA surveillance program. The committee stated that the surveillance
data are imperfect and that surveillance should be increased**.

**The committee voted**: **0 yes votes, 17 no votes, and 0
abstentions.**

3\. Are there other bovine neurological tissues that, if used in
consumer products (such as foods, dietary supplements, cosmetics, and
certain non-application drugs), could also pose a significant health
hazard? If so, what are the differences in relative degrees of
infectivity of these tissues?

**The committee voted: 17 yes votes, 0 no votes, and 0 abstentions**.
The committee passed on the second part of the question and referenced
their answer to #2.

4\. What physical, chemical, or biological factors of tissues and/or
processes should FDA consider in reviewing procedures that may have the
ability to reduce infectivity of bovine neurological tissues and
products containing bovine neurological tissues?

**Everything should be considered on a product by product case. One
committee member stated that most processing steps would not affect the
infectivity of prion protein. It was stated that this question is too
complicated and needs a separate meeting, ideally with presentations on
different processes which may be used to process these tissues and
manufacture products from them.**

5\. What tests are available to ascertain changes in infectivity in
products containing bovine neurological tissues as a result of
processing?

**There are two to three types of assays, bioassays including those in
transgenic mice, cell culture models and *in vitro* conversion assays
also test for the abnormal PRP protein. Confirmation dependent
immunoassay was mentioned. A member said that the best way to confirm
infectivity is through Western Blot, although it was stated earlier that
getting a representative sample is a problem with Western blotting
procedures. There are really no 'practical' tests available to measure
infectivity. It was stated that, like question 4, this is a very complex
question which may warrant a separate meeting (perhaps in conjunction
with question 4), ideally with presentations on how these tissues are
processed.**

6\. What level of reduction in infectivity is necessary to consider
products containing bovine neurological tissues non-infective or
\"safe\" for human use?

**There are multiple levels of reduction depending on the origin and the
sourcing of the material. Since we do not know the infective dose for
humans and the infective dose may vary based on individual genetic
composition, we should have a zero tolerance for the infectious unit
because any level of infectivity may be unacceptable.**

**One committee member stated that bovine brain, spinal cord, distal
ileum, and eye should not be allowed for use in products in the U.S.**