Use of Materials Derived from Cattle in Medical Products Intended for Use in Humans and Drugs Intended for Use in Ruminants, 1582-1619 [E6-22329]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 72, Number 8 (Friday, January 12, 2007)]
[Proposed Rules]
[Pages 1582-1619]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-22329]



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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 211, 226, 300, et al.



 Use of Materials Derived from Cattle in Medical Products Intended for 
Use in Humans and Drugs Intended for Use in Ruminants; Proposed Rule

Federal Register / Vol. 72, No. 8 / Friday, January 12, 2007 / 
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 211, 226, 300, 500, 530, 600, 895, and 1271

[Docket No. 2005N-0373]
RIN 0910-AF54


Use of Materials Derived from Cattle in Medical Products Intended 
for Use in Humans and Drugs Intended for Use in Ruminants

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
prohibit the use of certain cattle material in, or in the manufacture 
(including processing) of, drugs, biologics, and medical devices 
intended for use in humans and human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) (collectively, medical products for 
humans), and in drugs intended for use in ruminant animals (drugs for 
ruminants). FDA is also proposing new recordkeeping requirements for 
medical products for humans and drugs for ruminants that are 
manufactured from or otherwise contain material from cattle. FDA is 
proposing these actions as part of its continuing efforts to strengthen 
defenses against the potential risk of exposure to, and spread of, 
bovine spongiform encephalopathy (BSE) and related human disease in the 
United States.

DATES: Submit written or electronic comments on the proposed rule by 
March 13, 2007. Submit written comments on the information collection 
requirements by February 12, 2007. Requests for an informal hearing on 
the proposed ban related to medical devices must be submitted by 
February 12, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2005N-0373 
and RIN number 0910-AF54, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For detailed 
instructions on submitting comments and additional information on the 
rulemaking process, see section VII ``Effective Date and Opportunity 
for Public Comment'' in the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.
    Information Collection Provisions: To ensure that comments on the 
information collection are received, Office of Management and Budget 
(OMB) recommends that written comments be faxed to the Office of 
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 
202-395-6974.

FOR FURTHER INFORMATION CONTACT:
    For information concerning products regulated by the Center for 
Drug Evaluation and Research: Vikki Kinsey, Center for Drug Evaluation 
and Research (HFD-006), Food and Drug Administration, 5515 Security 
Lane, rm. 5110, Rockville, MD 20852, 301-443-5578, e-mail: 
vikki.kinsey@fda.hhs.gov.
    For information concerning products regulated by the Center for 
Biologics Evaluation and Research: Stephen M. Ripley, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, rm 594N, Rockville, MD 20852-1448, 
301-827-6210, e-mail: stephen.ripley@fda.hhs.gov.
    For information concerning products regulated by the Center for 
Devices and Radiological Health: Scott G. McNamee, Center for Devices 
and Radiological Health, Food and Drug Administration, 2094 Gaither 
Rd., rm. 230, Rockville, MD 20850, 240-276-0105, e-mail: 
scott.mcnamee@fda.hhs.gov.
    For information concerning products regulated by the Center for 
Veterinary Medicine: Michael J. Popek, Center for Veterinary Medicine 
(HFV-144), Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20855, 301-827-6462, e-mail: michael.popek@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
    A. Transmissible Spongiform Encephalopathies
    B. Bovine Spongiform Encephalopathy
    C. Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease
    D. BSE Risk Assessments
    1. Harvard-Tuskegee Study
    2. USDA Surveillance Program
    3. BSE Testing for Product Safety Purposes
    4. BSE Infectivity via Medical Products for Humans and Drugs for 
Ruminants
    E. Cattle Materials
    1. Specified Risk Material
    2. Small Intestine
    3. Mechanically Separated Beef
    4. Nonambulatory Disabled Cattle
    5. Cattle Not Inspected and Passed for Human Consumption
    6. Tallow and Tallow Derivatives
    7. Fetal Calf Serum
    8. Additional Requirements
    F. Medical Products for Humans and Drugs for Ruminants That May 
Contain Cattle Material
    1. Drugs for Humans
    2. Biologics for Humans
    3. HCT/Ps
    4. Medical Devices for Humans
    5. Drugs for Ruminants
III. USDA/FSIS IFR
IV. FDA Actions on BSE
    A. Regulations
    1. FDA 1997 Ruminant Feed Rule
    2. FDA/USDA Animal Feed ANPRM and FDA 2005 Animal Feed Proposed 
Rule
    3. Foods IFR
    4. Foods Recordkeeping/Access Final

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Rule
    B. FDA Guidance
V. Description of Proposed Rule
    A. Definitions
    B. Proposed Requirements for Prohibited Cattle Materials and 
Permission for an Exception or Alternative to These Requirements
    C. Tallow and Tallow Derivatives
    D. Proposed Requirements Regarding Extralabel Drug Use in Animals
    E. Proposed Recordkeeping Requirements
    1. Types of Records
    2. Proposed Periods for Records Retention
    3. Location of Records
VI. Legal Authority
VII. Effective Date and Opportunity for Public Comment
VIII. Analysis of Impacts
    A. Need for the Proposed Rule
    B. Scope of the Proposed Rule
    C. Costs of the Proposed Rule
    1. Potential Market Adjustments
    2. Cost of Requests for Exception or Alternatives to the Limitation 
on the Use of Prohibited Cattle Material
    3. Cost of Substitutes
    4. Recordkeeping Requirements of the Proposed Rule
    5. Labeling Costs for Drugs Prohibited from Extralabel Use
    6. Summary of the Cost for the Proposed Rule
    D. Benefits of the Proposed Rule
    1. Reduced Risk of Exposure to BSE Infectivity
    2. Value of the Potential Reduction of Human Illness
    E. Summary of the Potential Costs and Benefits of the Proposed Rule
    F. Regulatory Options Considered
    G. Regulatory Flexibility Analysis
IX. Paperwork Reduction Act Analysis
X. Environmental Impact Analysis
XI. Federalism
XII. References

I. Introduction

    On January 26, 2004, the U.S. Department of Health and Human 
Services announced its plan to establish new safeguards to strengthen 
existing firewalls against transmission of BSE in the United States. 
Consumption of products contaminated with the agent that causes BSE has 
been linked to the human disease variant Creutzfeldt-Jakob disease 
(vCJD). Current protections against the spread of BSE in the United 
States include:
     FDA's ruminant feed regulation (the 1997 ruminant feed 
rule) (62 FR 30936, June 5, 1997) (see section V.A.8 of this document 
for definition of ruminant),
     U.S. Department of Agriculture's (USDA's) Food Safety and 
Inspection Service (FSIS) interim final rule banning specified risk 
materials (SRMs) and certain other cattle material in human food (the 
USDA/FSIS IFR) (69 FR 1862, January 12, 2004; as amended, 70 FR 53043, 
September 7, 2005),
     FDA's interim final rule banning the use of SRMs and 
certain other cattle material in human food, including dietary 
supplements, and cosmetics (the Foods IFR) (69 FR 42256, July 14, 2004; 
as amended, 70 FR 53063, September 7, 2005), and
     Import controls.
    FDA also has requirements for establishment and maintenance of 
records concerning use of materials derived from cattle in human food 
and cosmetics (the Foods Recordkeeping/Access final rule) (71 FR 59653, 
October 11, 2006). In addition, FDA, in conjunction with USDA, issued 
an advance notice of proposed rulemaking (ANPRM) to solicit comment on 
additional measures under consideration, including measures related to 
animal feeds (the joint ANPRM) (69 FR 42288, July 14, 2004). On October 
6, 2005 (70 FR 58570), we issued a proposed rule that would prohibit 
certain cattle materials from all animal feed (FDA 2005 Animal Feed 
proposed rule).
    In this medical products proposed rule, FDA is proposing to 
prohibit use of SRMs and certain other cattle material in, or in the 
manufacture (including processing) of, medical products for humans and 
drugs for ruminants because of the risk of transmission of BSE. FDA is 
also proposing recordkeeping requirements for medical products for 
humans and drugs for ruminants that are manufactured from or otherwise 
contain material from cattle to ensure compliance with the prohibitions 
in this proposed rule. The proposed requirements are consistent with 
the requirements in the USDA/FSIS IFR and the Foods IFR, as well as 
those in the Foods Recordkeeping/Access final rule. The proposed 
requirements in this medical products proposed rule only apply to 
medical products for humans and drugs for ruminants. They do not apply 
to any other product regulated by FDA.

II. Background

A. Transmissible Spongiform Encephalopathies

    Transmissible spongiform encephalopathies (TSEs) are fatal 
neurodegenerative disorders that have been identified in humans and a 
number of animal species (e.g., cattle, sheep, goats, elk, deer, cats, 
and mink), but primarily in ruminants (i.e., animals that have a 
stomach with four compartments, such as cattle and buffalo). A TSE is 
characterized by a long incubation period, followed by a shorter course 
of neurological symptoms, followed by death (Ref. 1). Postmortem 
histopathology of the brain tissue from humans and animals with TSEs is 
characterized by a sponge-like appearance of the brain and deposits of 
abnormal forms of certain cell-associated proteins (normal prion 
proteins) in the brain.
    TSEs in humans include CJD, vCJD, Gerstmann-Str[auml]ussler-
Scheinker syndrome, kuru, fatal familial insomnia, and sporadic fatal 
insomnia (Ref. 8). Nonhuman TSEs include BSE in cattle, scrapie in 
sheep and goats, transmissible mink encephalopathy (TME) in mink, 
feline spongiform encephalopathy (FSE) in cats, and chronic wasting 
disease (CWD) in deer and elk (Ref. 8). Scrapie and CWD occur, and TME 
has occurred, in the United States. On December 23, 2003, USDA 
diagnosed BSE in an adult cow in the United States that had been 
imported from Canada. Since then, USDA has confirmed two other cases of 
BSE in adult cows in the United States. One cow, which was diagnosed on 
June 24, 2005, was born and raised in Texas. The other cow, which was 
diagnosed on March 15, 2006, had been on a farm in Alabama for less 
than a year. The Texas cow was 12 years old and the Alabama cow was 
determined to be more than 10 years old. Therefore, both cows were born 
before the 1997 ruminant feed rule was in place. USDA determined that 
no part of the animals entered the human food or animal feed chains.
    The pathogenesis of TSEs is poorly understood. TSE agents resist 
complete inactivation by treatments that destroy conventional 
microorganisms, like bacteria and viruses. Thus, conventional 
microorganisms are not likely causes of TSEs (Ref. 9). The most widely 
accepted explanation for TSEs, the prion theory, suggests that the 
infectious agents of TSEs are abnormally folded forms of normal prion 
proteins (Refs. 10 and 11). Normal prion protein genes are found widely 
in nature. In mammals, normal prion proteins are primarily expressed in 
neurons, but also can be found in other tissues in lower 
concentrations, depending on the mammalian species (Ref. 12). It is not 
well understood how the abnormal folding of prion proteins occurs or 
why hosts cannot efficiently dispose of or develop immunity to these 
proteins.
    The current lack of an antemortem diagnostic test for TSEs in 
either humans or animals limits surveillance

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for these diseases, studies of disease pathogenesis, and other research 
efforts. Diagnosis is confirmed by special postmortem examination of 
brain tissue by identification of abnormal prion proteins in advanced 
stages of the disease. At earlier stages of disease development, 
abnormal prion proteins are undetectable in brain tissue. Presently, 
there are no effective treatments for TSEs, and all TSEs are invariably 
fatal (Ref. 1).

B. Bovine Spongiform Encephalopathy

    BSE is a TSE of cattle with a long incubation period (up to 8 years 
or longer), most likely acquired following consumption of an animal 
product containing the BSE infectious agent (Refs. 13 and 14). The 
British Ministry of Agriculture, Fisheries and Food (now known as the 
Department for Environment, Food, and Rural Affairs) first recognized 
BSE as a distinct disease in November 1986. The clinical signs of BSE 
include behavioral, gait, and postural abnormalities. The disease 
usually presents in cattle as increased apprehension, increased 
reaction to sound and touch, and a swaying gait. These signs are 
accompanied by subtle changes in the normal behavior of the cow, such 
as separation from the herd while at pasture, disorientation, staring, 
and excessive licking of the nose or flanks. The disease progresses to 
stumbling and falling, and ends with seizures, coma, and death (Ref. 
15).
    Experiments indicate that the infectious dose for cattle is very 
low. One gram of homogenized brain from affected cattle caused BSE in 7 
out of 10 calves fed the brain sample. Six years after oral consumption 
of lower doses of brain material, 3 of 15 calves fed 0.1 gram, and 1 of 
15 calves fed 0.01 gram, and 1 of 15 calves fed 0.001 gram (1 mg) of 
brain sample had developed the disease. This experiment is ongoing 
(Ref. 16).
    Epidemiological studies have characterized the outbreak of BSE in 
the United Kingdom as a prolonged epidemic in which early cases were 
seen simultaneously at various locations, but with all occurrences 
presumably due to a common point source of infection (Ref. 17). 
Consistent with this observation, the subsequent spread of BSE was 
associated with the feeding of meat-and-bone-meal from rendered BSE-
infected cattle to non-infected cattle (Ref. 17). It appears likely 
that the BSE agent was transmitted among cattle at an increasing rate 
by ruminant-to-ruminant feeding until the United Kingdom ban on such 
practices went into effect in 1988 (Ref. 13). The United Kingdom 
instituted a ruminant-to-ruminant feed ban to stop the cycle of 
infection, restrict the geographic spread of the disease, and eliminate 
potential sources of new infections. Since BSE was first identified in 
the United Kingdom, approximately 185,000 cattle have been diagnosed 
with the disease there (Ref. 18). The precautionary slaughter of 
millions of British cows and increasingly stringent prohibitions on 
certain animal feeding practices appear to have slowed, but not 
eradicated, the BSE epidemic in the United Kingdom. In 1992 (the peak 
year of the epidemic), there were over 37,000 cases of BSE in the 
United Kingdom; in 2005, there were 225 cases (Ref. 18).
    The introduction of BSE into other countries presumably originated 
from their import of cattle, or animal feed made with cattle material, 
from the United Kingdom during the BSE epidemic (Ref. 13). In addition 
to the United Kingdom, BSE has been detected in indigenous cattle in 
Austria, Belgium, Canada, the Czech Republic, Denmark, Finland, France, 
Germany, Greece, Israel, Italy, Japan, Liechtenstein, Luxembourg, the 
Netherlands, Poland, Portugal, the Republic of Ireland, Slovakia, 
Slovenia, Spain, Sweden, Switzerland and the United States (Ref. 19).

C. Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease

    Creutzfeldt-Jakob Disease (CJD) is a sporadic disease of humans 
that exists throughout the world with an annual incidence of 
approximately one case per million population (Ref. 10). The highest 
death rates in the United States and the United Kingdom occur in 
individuals between the ages of 60 and 70 (Ref. 20). Death generally 
occurs after less than a year of progressive neurological deterioration 
(Ref. 10). Early symptoms typically include changes in sleeping and 
eating patterns, followed by inappropriate behavior and eventual 
dementia, lack of coordination, and myoclonic spasms. CJD is always 
fatal (Ref. 20). The cause of sporadic CJD is not fully understood, but 
genetic susceptibility may play a role (Ref. 10). CJD has been 
inadvertently transmitted between humans during medical treatment or 
diagnostic procedures via contaminated neurosurgical instruments, 
transplants of dura mater and corneas, and injection of pituitary 
extract (Ref. 10).
    In April 1996, British scientists reported a previously undetected 
new vCJD in young patients, with symptoms somewhat different from 
sporadic CJD (Refs. 21 and 22). All cases of vCJD had histopathologic 
evidence of spongiform changes in the brain, but also showed formation 
of ``florid'' plaques (a core of amyloid protein with surrounding halos 
of vacuoles) not typically seen in other forms of CJD (Ref. 10). 
Clinically, vCJD usually begins with a psychiatric presentation, such 
as depression, anxiety, nightmares, or hallucinations. These symptoms 
are followed by memory impairment, then dementia in the late stages. 
The clinical course generally ranges from 9 months to 3 years before 
death occurs (Ref. 23). The probable incubation period for vCJD in 
humans may range from 5 to more than 20 years (Ref. 39).
    Scientists have concluded that exposure to the BSE agent is the 
most plausible explanation for the occurrence of vCJD (Refs. 24 through 
27). Monkeys (genetically the closest animal model to humans) 
inoculated with samples of brain from BSE-infected cattle have been 
found to develop a TSE that is histopathologically similar to vCJD 
(Ref. 28), as have mice inoculated or fed with BSE-infected tissue 
(Ref. 29). Studies have shown that abnormal prion proteins from vCJD 
patients are molecularly similar to abnormal prion proteins from BSE-
infected cattle, but different from abnormal prion proteins from 
patients with CJD (Ref. 23). Although the exact route of exposure is 
not known, most scientists believe that vCJD in humans has been caused 
by consumption of cattle products contaminated with the agent that 
causes BSE (Refs. 20, 30, and 31). There is thought to be a 10- to 
10,000-fold increase in the amount of infectious material needed to 
cause illness in humans as compared with cattle because of the species 
barrier, although the European Commission's Scientific Steering 
Committee cautioned that this range is uncertain and in an unlikely, 
but worst case scenario, the species barrier may not exist (Ref. 40).
    As of August 2006, 162 probable and confirmed cases of vCJD have 
been reported in the United Kingdom (Ref. 32). In addition, there have 
been 15 vCJD cases in France, 3 in Ireland, 2 in the United States ,and 
1 each in Canada, Italy, the Netherlands, Portugal, Japan, Spain, and 
Saudi Arabia (Refs. 33 through 38 and 70). The two cases in the United 
States, one of the three from Ireland, and the single cases from Canada 
and Japan are likely due to the individual's exposure to BSE in the 
United Kingdom (Refs. 34, 36, and 70).
    The infectious dose for humans is not known. Despite widespread 
exposure in the United Kingdom to BSE-contaminated meat products, only 
a very small percentage of the exposed population has been diagnosed 
with vCJD to date. This may reflect a partial

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species barrier to disease transmission from cattle to humans via the 
oral route of exposure (Ref. 40).

D. BSE Risk Assessments

1. Harvard-Tuskegee Study
    In 1998, USDA asked the Harvard Center for Risk Analysis (HCRA) and 
the Center for Computational Epidemiology at Tuskegee University to 
evaluate United States measures to prevent the spread of BSE to animals 
and humans if it were to occur in this country. The Harvard-Tuskegee 
risk assessment (the Harvard-Tuskegee study determined that the United 
States was highly resistant to any proliferation of BSE or a similar 
disease (Ref. 41). The risk assessment model also demonstrated that 
certain new control measures could reduce the small risk even further.
    The Harvard-Tuskegee study involved a probabilistic simulation 
model to determine the consequences of introducing BSE into the U.S. 
cattle population. This simulation indicated that, in a hypothetical 
situation in which 10 infected cattle were imported into the United 
States, on average only 4 new cases of BSE would arise, and the disease 
would be eliminated in 20 years. The Harvard-Tuskegee study determined 
that these new cases of BSE would most likely arise in the United 
States from incomplete compliance with the FDA 1997 ruminant feed rule 
(see section III.A.1 of this document), and also concluded that an 
epidemic of BSE in this country resulting from scrapie, CWD, or another 
TSE is unlikely.
    The Harvard-Tuskegee study estimated the number of cattle 
infectious doses that might be available for human exposure, but it did 
not estimate the likelihood of human disease from this exposure because 
the relationship between the two is not known. According to the study, 
the estimated total infectivity available for human exposure from the 
importation of 10 infected cattle is 39 cattle infectious doses over 20 
years. The Harvard-Tuskegee study determined that the greatest sources 
of infectivity to consumers from food are direct consumption of cattle 
brain and spinal cord and also meat that contains central nervous 
system tissue from advanced meat recovery systems. The Harvard-Tuskegee 
study did not address potential human exposure to the BSE agent through 
food, medical products for humans, or drugs for ruminants that contain 
ingredients of bovine origin, such as gelatin (from bovine bones and 
hides), heparin and surfactants (from bovine lung), insulin (from 
bovine pancreas), hormones (from bovine urine and serum), enzymes (from 
bovine intestine), or glycosphingolipids (from bovine brains).
    The Harvard-Tuskegee study identified three pathways that could 
lead to cattle or human exposure to the BSE agent through food or feed: 
(1) Noncompliance with the FDA 1997 ruminant feed rule prohibiting the 
use of certain proteins in feed for cattle and other ruminants; (2) 
rendering of animals that die on the farm and use (through illegal 
diversion or cross-contamination) of the rendered product in ruminant 
feed; and (3) the inclusion of high-risk tissues from cattle, such as 
brain and spinal cord, in products for human oral consumption. 
Evaluation of potential risk mitigation measures in the study found 
that a prohibition against rendering of animals that die on the farm 
would reduce the potential cases of BSE following hypothetical exposure 
by 82 percent. In addition, a ban on including SRMs (defined in the 
study as brain, spinal cord, gut, eyes, and advanced meat recovery 
products without reference to age of the animals at slaughter) in human 
and animal food would reduce potential BSE cases in cattle by 88 
percent and potential human exposure to BSE by 95 percent. The Harvard-
Tuskegee study also noted the value of ensuring that low-risk cattle 
tissues are not cross-contaminated with high-risk tissue.
    USDA recently released an updated version of the BSE risk 
assessment model and report, completed by HCRA (Ref. 42). USDA 
requested that HCRA utilize an updated risk assessment model to 
evaluate the impact of measures implemented after the discovery of a 
BSE-positive cow in Washington State in December 2003, and 
recommendations made by an international BSE panel. The updated risk 
assessment estimates that the measures adopted by USDA in January 2004 
will result in a 99.6 percent (at the mean) relative reduction in 
potential human exposure to the BSE agent through consumption of beef 
and beef products.
2. USDA Surveillance Program
    The USDA has led targeted BSE surveillance efforts since 1990. On 
June 1, 2004, in response to a recommendation from the international 
scientific review panel that assessed USDA's investigation into the 
discovery of a BSE positive cow in Washington State on December 23, 
2003, USDA began an enhanced BSE surveillance effort. This effort 
continued to focus on the targeted subpopulation of cattle, with a goal 
to obtain as many samples as possible from the targeted population, to 
help determine whether BSE is present in the United States. Targeted 
cattle are defined as nonambulatory cattle; cattle exhibiting signs of 
a central nervous system disorder; cattle exhibiting other signs that 
may be associated with BSE, such as emaciation or injury; or dead 
cattle. To date, USDA has sampled more than 700,000 targeted cattle, 
only two of which were positive for BSE (Ref. 43). A detailed analysis 
of surveillance data obtained through March 2006 concluded that the 
prevalence of BSE in the United States is less than one infected animal 
per million adult animals (Ref. 7).
3. BSE Testing for Product Safety Purposes
    No validated antemortem tests for BSE exist. The currently 
available postmortem tests, although useful for disease surveillance 
(i.e., determining the rate of disease in the population of cattle), 
are not appropriate as safety indicators for food, medical products for 
humans, or drugs for ruminants. This is due, in part, to limitations on 
the existing testing methods, which rely on the use of postmortem brain 
tissue. Experimental evidence demonstrates that, in cattle infected 
orally, certain potentially infective tissues (such as the distal ileum 
and tonsil) are the first tissues to accumulate infectivity in the 
incubation period and this infectivity occurs prior to any demonstrated 
infectivity in brain tissue (Refs. 3, 45, and 46). Therefore, tests 
conducted on brain tissue may not reflect accurately the potential 
infectivity in other tissues that develop infectivity earlier, such as 
the distal ileum. Development of effective safety indicators for food, 
medical products for humans, and drugs for ruminants will require 
improved understanding of the pathogenesis of the disease and improved 
laboratory methods.
4. BSE Infectivity via Medical Products for Humans and Drugs for 
Ruminants
    While BSE is usually a concern identified with food safety or 
animal health, medical products for humans or drugs for ruminants, 
because of the ways they are used or come into contact with the body, 
provide another route for human or ruminant exposure to the BSE 
infectious agent. Medical products for humans and drugs for ruminants 
may contain or be made using a variety of cattle-derived materials. 
Examples of materials that are sometimes derived from cattle and that 
are used in, or in the manufacture of, these products include gelatin, 
heparin, surfactants, hormones, enzymes,

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glycosphingolipids, amino acids, glycerol, detergents, blood, collagen, 
fetal calf serum, bovine meat, and tallow and tallow derivatives.
    The route by which TSE-contaminated material is introduced into a 
host is an important determinant of TSE transmissibility. Animal 
studies have indicated that injection of a TSE agent directly into the 
brain or spinal cord is the most efficient route of transmission, 
followed by intravenous, intraperitoneal, and subcutaneous routes, and 
then by the oral route (Refs. 2 and 47 through 56). Topical 
administration on intact skin is unlikely to lead to disease 
transmission, but topical products presumably can cause disease if 
administered to skin with cuts, abrasions, or open wounds, or if 
administered to the eyes or other mucosal tissue (Refs. 57 through 59).
    Currently, no validated method for testing products for humans and 
ruminants for the agent that causes BSE is available; therefore, we do 
not have a means of distinguishing products that contain infectious 
material from products that do not. End users (e.g., consumers, 
physicians, farmers, veterinarians) also often are not able to 
determine which products contain prohibited cattle materials and which 
products do not because such information is generally not included in 
product labels or labeling. For example, rendered material including 
brain and spinal cord may become an ingredient in a medical product for 
humans or a drug for ruminants, although its presence may not be 
indicated on the label. Furthermore, end users have no way to determine 
whether cattle material in these products was sourced from 
nonambulatory disabled cattle or from cattle that were not inspected 
and passed for human consumption.
    Based on what is known about transmission of BSE, there is risk of 
occurrence of vCJD in humans and of TSE in ruminants from the use of 
high-risk cattle-derived materials in medical products for humans and 
drugs for animals. While the results from USDA's ongoing testing are 
reassuring and so far have identified only two additional BSE-infected 
cows in the United States, one cannot rule out the possibility of 
future discovery of additional positive animals in the United States or 
in a country allowed to export cattle material to the United States, or 
of a future introduction of BSE. To provide consistent protection 
across the range of FDA-regulated products, it is necessary to put in 
place measures to reduce further the risk of spread of BSE in cattle 
and the risk of vCJD in humans. These risks may be reduced by 
restricting the use of high-risk cattle materials in the manufacture of 
drugs for ruminants and medical products for humans, similar to 
existing restrictions for food and cosmetics.

E. Cattle Materials

    This proposed rule would apply to medical products for humans and 
drugs for ruminants that are manufactured from or otherwise contain 
certain cattle material. This section discusses the reasons for FDA's 
decision to propose to restrict the use of such material in medical 
products for humans and drugs for ruminants.
1. Specified Risk Materials
    This proposed rule would designate SRMs as prohibited cattle 
materials in medical products for humans and drugs for ruminants. 
Specified risk materials would be defined, consistent with the Foods 
IFR (69 FR 42256 at 42259 and 70 FR 53063 at 53064 through 53065; 
discussed in section IV.A.3 of this document) and the USDA/FSIS IFR (69 
FR 1862 and 70 FR 53043; discussed in section III of this document) as 
the brain, skull, eyes, trigeminal ganglia (clusters of nerve cells 
connected to the brain that lie close to the exterior of the skull), 
spinal cord, vertebral column (excluding the vertebrae of the tail, the 
transverse processes of the thoracic and lumbar vertebrae, and the 
wings of the sacrum), and dorsal root ganglia (clusters of nerve cells 
attached to the spinal cord that are contained within the bones of the 
vertebral column) of cattle 30 months and older, and the tonsils and 
distal ileum of the small intestine of all cattle.
    In a pathogenesis study in which cattle were orally inoculated with 
BSE and then one to three animals were killed and tested at sequential 
4- to 6-month intervals, Wells et al. found infectivity using a mouse 
bioassay at 32 months postinoculation in brain, spinal cord, dorsal 
root ganglia, and trigeminal ganglia (Ref. 3). Unequivocal clinical 
disease was first observed at 38 months postinoculation. It is not 
known how representative these results are, given the extremely small 
number of cattle tested and the limitations inherent in the mouse 
bioassay. It also should be noted that only one animal was tested at 26 
months postinoculation and no testing was performed again until 32 
months postinoculation. Thus, no conclusion can be drawn as to when, in 
the period between 26 and 32 months postinoculation, infectivity 
appeared in the tested tissues. The studies will continue for several 
more years, using a more sensitive cattle assay, to determine if any of 
the tissues that initially did not appear to be infective actually 
contain low levels of infection (Refs. 2 through 6 and 60). Infectivity 
has also been found at 6 months postinoculation in distal ileum and at 
10 months postinoculation in tonsils (Refs. 4 and 60).
    In cattle infected with BSE under field conditions (i.e., not 
intentionally exposed to BSE as part of an experiment), infectivity has 
been found in the brain, spinal cord, and retina of the eye in animals 
with clinical disease (Ref. 60). The Scientific Steering Committee of 
the European Union (Ref. 31) has reported on the proportion of total 
infectivity in various tissues. They estimate that in an animal with 
clinical disease, approximately 64 percent of the infectivity is in the 
brain, 26 percent is in the spinal cord, 4 percent is in the dorsal 
root ganglia, 2.5 percent is in the trigeminal ganglia, and 3 percent 
is in the distal ileum. The eyes are estimated to contain less than 1 
percent of the infectivity. In 2003, P. J. Comer and P. J. Huntly 
reported generally similar estimates of infectivity (i.e., 60.2 percent 
in brain, 24.1 percent in the spinal cord, 3.6 percent in the dorsal 
root ganglia, 2.4 percent in the trigeminal ganglia and 9.6 percent in 
the distal ileum) (Ref. 44).
    Clinical cases of BSE in cattle under 30 months old are rare. For 
example, according to the United Kingdom's Department of Environment, 
Food and Rural Affairs, among the birth cohort of cattle in the United 
Kingdom that had the highest incidence of BSE (those born in 1987-88), 
cattle under 3 years old represented less than 0.16 percent of cattle 
with BSE (61 out of 39,140 cattle with BSE) (Ref. 61). Another report, 
looking at selected herds whose ages were known, found that in the 
first 6 months of 1989 and 1990, the BSE incidence in 2-year-old cattle 
(0.04 percent in 1989 and 0.05 percent in 1990) was approximately 15-
fold lower than that in 3-year-old cattle (0.56 percent in 1989 and 
0.86 percent in 1990), and was 45- to 75-fold lower than the incidence 
in 4-year-old cattle (2.83 percent in 1989 and 2.76 percent in 1990) 
(Ref. 62). Two-year-old cattle represented only about one-half of 1 
percent of the total BSE cases in the selected herds in those 6-month 
periods. The incidence in 2-year-old cattle (0.01 percent) decreased 
considerably in 1991, presumably reflecting the fact that they were 
born after July 1988, when the United Kingdom instituted measures 
prohibiting the use of meat and bone meal in cattle feed.
    We recognize that certain tissue from infected animals will be 
infectious a number of months before the animals exhibit clinical 
symptoms. However, in

[[Page 1587]]

BSE, as in other TSEs, the total amount of infectivity in an animal 
increases throughout the incubation period reaching the highest load 
when an animal begins to demonstrate clinical signs (Ref. 44). Because 
of this evidence combined with the very low incidence of clinical BSE 
in cattle younger than 30 months, we are proposing, consistent with the 
Foods IFR (69 FR 42256 at 42259) and the USDA/FSIS IFR (69 FR 1862), 
that brain, skull, eyes, trigeminal ganglia, spinal cord, vertebral 
column (excluding the vertebrae of the tail, the transverse processes 
of the thoracic and lumbar vertebrae, and the wings of the sacrum), and 
dorsal root ganglia should be considered SRMs only in cattle 30 months 
and older. We include the skull and the vertebral column in the list of 
SRMs because, even though they have not been shown to harbor BSE 
infectivity, they contain tissues (i.e., brain and spinal cord) that 
have been shown to be infectious. We did not include, consistent with 
the Foods IFR (69 FR 42256 at 42259) and the USDA/FSIS IFR (69 FR 1862 
at 1868), the vertebrae of the tail, the transverse processes of the 
thoracic and lumbar vertebrae, and the wings of the sacrum as SRMs with 
the rest of the vertebral column because they do not contain spinal 
cord or dorsal root ganglia. As the science and epidemiology on this 
issue develop, FDA may find it necessary through future rulemaking to 
modify the tissues classified as SRMs and the age at which these 
tissues are classified as SRMs.
    Based on the previously mentioned experimental evidence indicating 
that tonsils become infective by 10 months postinoculation and distal 
ileum by 6 months postinoculation (Refs. 3 and 4), we are proposing, 
consistent with the Foods IFR (69 FR 42256 at 42259 and 70 FR 53063 at 
53064 through 53065) and USDA/FSIS IFR (69 FR 1862 and 70 FR 53043), 
that the tonsil and distal ileum of the small intestine of all cattle 
be considered SRMs.
2. Small Intestine
    The small intestine is not considered prohibited cattle material if 
the distal ileum is removed by a procedure that removes at least 80 
inches of the uncoiled and trimmed small intestine as measured from the 
caeco-colic junction and progressing proximally towards the jejunum or 
by a procedure that the establishment can demonstrate is equally 
effective in ensuring complete removal of the distal ileum. In this 
medical products proposed rule, we are proposing to prohibit the use of 
small intestine of all cattle in medical products for humans and drugs 
for ruminants if procedures that completely remove the distal ileum are 
not used. This provision is consistent with USDA (70 FR 53043) and FDA 
(70 FR 53063) requirements. .
3. Mechanically Separated Beef
    Mechanically Separated (Species) is a standardized food defined by 
USDA in 9 CFR 319.5 (see section V.A of this document for the proposed 
definition of mechanically separated beef). The standard does not limit 
the amount of spinal cord and dorsal root ganglia allowed in vertebral 
column used to produce the product. Consequently, mechanically 
separated beef may contain concentrated amounts of such tissues. 
Because we are proposing that spinal cord, dorsal root ganglia and 
vertebral column be considered SRMs, we are also proposing, consistent 
with the USDA/FSIS and Foods IFRs (69 FR 1862 at 1866 through 1867 and 
69 FR 42256 at 42259), to include mechanically separated beef as a 
prohibited cattle material.
4. Nonambulatory Disabled Cattle
    Experience has shown that nonambulatory disabled cattle (see 
section V.A of this document for the proposed definition) are the 
population at greatest risk for harboring BSE. Surveillance data in the 
European Union in 2002 showed that there were 29 positive/10,000 tests 
for BSE among healthy-appearing cattle of all ages and 148 positive/
10,000 tests for BSE among nonambulatory animals of all ages (Ref. 63). 
In Switzerland, sampling of particular populations of cattle revealed 
that BSE-positive animals were 49 to 58 times more likely to be found 
in the nonambulatory population than in the population selected for 
passive surveillance (Ref. 64). The Harvard-Tuskegee study estimated 
that, following importation of 10 infected cattle, a prohibition 
against rendering animals that die on the farm (these animals could be 
nonambulatory disabled) would decrease the number of new cases of BSE 
by 82 percent.
    Because typical clinical signs of BSE cannot always be observed in 
nonambulatory disabled cattle, and because evidence has indicated these 
cattle are more likely to have BSE than apparently healthy cattle, FDA 
is proposing, consistent with the Foods IFR (69 FR 42256 at 42259), to 
include material from nonambulatory disabled cattle as prohibited 
cattle materials. This proposal is also consistent with USDA's 
requirement that all nonambulatory disabled cattle presented for 
slaughter be condemned (69 FR 1862 at 1870 and 1871).
5. Cattle Not Inspected and Passed for Human Consumption
    Cattle that have not been inspected (see section V.A of this 
document for the proposed definition) are at higher risk of having BSE, 
as well as other diseases, because they will not have been examined by 
USDA for their disease status in general and potential for harboring 
BSE in particular. In addition, such cattle are likely to have died on 
the farm or en route to slaughter, and these animals are not eligible 
for inspection by USDA. For cattle that are inspected but not passed, a 
regulatory authority (USDA or other) has made a determination that they 
are not appropriate for use in human food (69 FR 42256 at 42259). Such 
a determination may be based, among other things, on evidence of a 
neurological disorder associated with a higher risk of BSE. Moreover, 
material from cattle not inspected or inspected and not passed for 
human consumption is prohibited from human food (69 FR 42256 at 42259). 
In this rulemaking, FDA is proposing to extend this prohibition to 
medical products for humans and drugs for ruminants. By requiring that 
material from cattle for use in medical products for humans and drugs 
for ruminants be inspected and passed for human consumption, we would 
minimize the risk to humans and ruminants of exposure to the agent that 
causes BSE.
6. Tallow and Tallow Derivatives
    Tallow is an animal-derived hard fat that has been heat processed; 
most tallow is derived from cattle. In this proposed rule, we use the 
term tallow to refer only to tallow derived from cattle. Any risk of 
BSE transmission from tallow is a result of protein that is present as 
an impurity in the tallow. Taylor et al. (Refs. 65 and 66) found in 
rendering studies with abnormal prion protein that the prion protein 
did not preferentially migrate into the fat fraction, but remained with 
the protein fraction. Therefore, there is no reason to believe that 
tallow is likely to contain unusually high amounts of prion protein as 
a constituent of the insoluble impurities fraction that remains in 
tallow after rendering. Taylor et al. (Refs. 65 and 66) also reported 
that the various rendering processes used for tallow production in the 
United Kingdom were sufficient to produce tallow that did not result in 
infection when injected into the brains of mice, even though the 
starting material was highly spiked with the scrapie agent. Wilesmith 
et al. (Ref. 67) noted that the geographical variation in the incidence

[[Page 1588]]

of BSE in the United Kingdom was not consistent with the use of tallow 
in cattle feed and concluded that the most likely source of infection 
in cattle was BSE-contaminated meat and bone meal.
    The World Organisation for Animal Health (OIE) (formerly the Office 
International des Epizooties), the international animal health standard 
setting body, categorizes tallow with insoluble impurities of no more 
than 0.15 percent as protein-free tallow and indicates that tallow that 
meets this standard can be safely consumed by animals, regardless of 
the starting materials (Ref. 68). FDA's Transmissible Spongiform 
Encephalopathies Advisory Committee (TSEAC) considered the safety of 
tallow in 1998 (Ref. 69). Although members of the TSEAC indicated that 
tallow is a food with extremely low risk of transmitting BSE to humans 
or animals, they did not see a need to change FDA's recommendation that 
tallow not be sourced from cattle born, raised, or slaughtered in 
countries where BSE is known to exist.
    Based on the research and the opinions noted previously that show 
that tallow is inherently a low risk material because of the procedures 
by which it is manufactured, we are proposing to permit tallow from any 
country to be used in medical products for humans and drugs for 
ruminants, as we have for human food and cosmetics (69 FR 42256 at 
42260 and 42261), if it contains no more than 0.15 percent insoluble 
impurities regardless of the starting materials or if it otherwise 
complies with these regulations (e.g., made without the use of any 
prohibited cattle materials). We recognize that the TSEAC did not see a 
need to change FDA's tallow import policy, which recommended against 
use of tallow from cattle born, raised, or slaughtered in countries 
where BSE is known to exist. However, the TSEAC was not asked to 
provide recommendations regarding import of tallow that met our 
proposed requirements. We believe we are proposing a tallow standard 
for medical products for humans and drugs for ruminants that is 
consistent with statutory safety standards and the recommendations by 
OIE with respect to bovine-derived tallow to prevent BSE in cattle and 
vCJD in humans.
    Distinct from tallow are tallow derivatives. These derivatives are 
produced by subjecting tallow to chemical processes (hydrolysis, trans-
esterification, or saponification) that involve high temperature and 
pressure. The TSEAC considered tallow derivatives in 1998 (Ref. 69) and 
determined that the rigorous conditions of manufacture are sufficient 
to further reduce the BSE risk in tallow derivatives. In addition, the 
OIE also recommends that derivatives of protein-free tallow be freely 
traded among countries because they pose an insignificant BSE risk to 
animals (Ref. 68). Because we believe that tallow has negligible risk 
of transmitting BSE, and tallow derivatives undergo additional 
processing, we do not believe that tallow derivatives pose a risk of 
transmitting the agent that causes BSE to humans. Therefore, we are 
proposing, consistent with the Foods IFR (69 FR 42256 at 42261), that 
tallow derivatives not be considered a prohibited cattle material. FDA 
proposes to clarify, as in the amendments to the Foods IFR (70 FR 
53063), that the ``no more than 0.15 percent insoluble impurities'' 
restriction for tallow does not apply to tallow derivatives.
7. Fetal Calf Serum
    Current evidence suggests that cow-to-calf transmission of BSE is 
unlikely to occur (Refs. 14 and 46). Therefore, the serum of fetal 
calves is unlikely to contain any BSE infectious material, irrespective 
of the age of the mother. However, because fetal calf serum (FCS) is 
generally collected from fetuses of dairy cows culled for low milk 
production or for health reasons, these cows are often considerably 
older than 30 months. FDA believes that manufacturers commonly take 
appropriate steps to prevent contamination of the FCS with specified 
risk materials from the mother. These steps include the normal dressing 
procedures used in slaughter houses, consisting of removing the uterus 
completely from the carcass and other viscera of cows that were 
inspected and passed, taking it to a separate space free of prohibited 
cattle materials for cardiac puncture, and collecting the fetal blood 
in a closed collection system using aseptic technique. Other procedures 
could also be used to provide adequate assurance that contamination has 
been prevented.
8. Additional Requirements
    If the agency finds that additional protections are needed for 
specific products or classes of products covered by applications (e.g., 
products with direct routes of exposure into the bloodstream or neural 
tissue such as injectable, ophthalmic, intranasal, or implanted FDA-
regulated products), it intends to provide those protections through 
the application review process or through other means, such as special 
controls for Class II devices. The agency believes it is possible that 
injectable, ophthalmic, intranasal, or implanted FDA-regulated products 
that contain cattle material other than prohibited cattle materials and 
that do not have an FDA approval covering use of that material may 
appear to be adulterated or misbranded under certain circumstances. If 
the agency finds that classes of such products or specific products do 
not meet the applicable statutory standards, it may take action even if 
the products comply with the requirements in this proposed regulation.

F. Medical Products for Humans and Drugs for Ruminants That May Contain 
Cattle Material

1. Drugs for Humans
    Under this proposed rule, drugs for humans cannot be manufactured 
from or otherwise contain prohibited cattle materials without written 
permission from FDA. For drugs subject to applications, the agency may 
provide additional protections through the application review process 
on a case-by-case basis to ensure that the products are safe and 
effective for their intended uses under section 505 of the Federal 
Food, Drug and Cosmetic Act (the act) (21 U.S.C. 355) and safe, pure, 
and potent under section 351 of the Public Health Service Act (the PHS 
Act) (42 U.S.C. 262). For drugs not subject to applications, if the 
agency finds that specific products or product classes do not meet the 
applicable statutory standards regarding adulteration and misbranding, 
it may take action even if the products comply with the requirements in 
this proposed rule.
    Many approved human drugs, as well as investigational human drugs, 
contain ingredients that are derived from cattle. Over the last 10 
years, FDA has maintained a database that identifies these drugs and 
their cattle-derived ingredients. Based on the information in this 
database, we are aware of no approved drugs and no investigational 
drugs that are manufactured with cattle material that would be 
prohibited under this proposed rule based on the type of cattle tissue 
used.\1\
---------------------------------------------------------------------------

    \1\All manufacturers would have to ensure that any cattle 
material they use comes from cattle that are inspected and passed 
and otherwise complies with the other requirements proposed in this 
rule.
---------------------------------------------------------------------------

    In addition to human drugs with approved applications, a number of 
human drugs are marketed without an approved application and, 
therefore, have not been subject to the new drug application (NDA) 
review process (e.g., products marketed under FDA's over-the-counter 
(OTC) monograph system, Active Pharmaceutical Ingredients,

[[Page 1589]]

homeopathic preparations, or products that purport to be 
``grandfathered''). Although FDA's database of these products is 
incomplete, some of them may contain cattle materials that would be 
prohibited under this proposed rule. The requirements proposed in this 
rulemaking apply to all drugs for humans, including those marketed 
without an approved application.
2. Biologics for Humans
    Many biological products are manufactured with, or otherwise use, 
cattle-derived material because this material can provide necessary 
nutrients for cell growth. For example, microorganisms used for vaccine 
manufacture are typically grown under controlled conditions in media 
that may contain cattle materials. Animal-derived products used in 
vaccine manufacture include amino acids, glycerol, detergents, gelatin, 
enzymes, and blood. Cattle skeletal muscle is used to prepare broths 
used in certain complex media.
    Many microorganisms that are difficult to grow and cells that are 
used to propagate viruses require serum in the growth media, which is 
typically derived from cattle blood. Cattle-derived materials (e.g., 
fetal calf serum, insulin, aprotinin, enzymes) are often used in cell 
culture techniques to manufacture hematological, cell, and gene-therapy 
products.
    Manufacturers of licensed products and sponsors of investigational 
new drug products are currently requested to provide, in their 
biologics license application (BLA) or investigational new drug 
application (IND), information regarding the source of all bovine-
derived materials used in the manufacture of their product. This 
information is reviewed by FDA along with other information provided in 
the application. SRMs are not ordinarily used in the manufacture of 
biological products. Biological products that are not intended for use 
in or on the body (e.g., in vitro diagnostics) would not be subject to 
the provisions of this proposed rule.
3. HCT/Ps
    This proposed rule would affect all HCT/Ps. HCT/Ps are defined in 
part 1271 (21 CFR part 1271) as ``articles containing or consisting of 
human cells or tissues that are intended for implantation, 
transplantation, infusion, or transfer into a human recipient. Examples 
of HCT/Ps include, but are not limited to, bone, ligament, skin, dura 
mater, heart valve, cornea, hematopoietic stem/progenitor cells derived 
from peripheral and cord blood, manipulated autologous chondrocytes, 
epithelial cells on a synthetic matrix, and semen or other reproductive 
tissue'' (Sec.  1271.3(d)). Certain exceptions apply (Sec.  
1271.3(d)(1) through (d)(7)).
    HCT/Ps are regulated according to a tiered, risk-based framework. 
HCT/Ps meeting the criteria listed in Sec.  1271.10 (e.g., minimally 
manipulated, intended for homologous use only (i.e., perform the same 
basic function(s) in the recipient as in the donor), not combined with 
a drug or device, and not having a systemic effect) are regulated 
solely under the authority of section 361 of the PHS Act (42 U.S.C. 
264). These ``361'' HCT/Ps are required to comply only with the 
applicable requirements in part 1271. Premarket review is not required 
for such products; therefore, FDA does not review any information 
regarding cattle-derived material that might be used in such products. 
This proposed rule would ban the use of prohibited cattle material in 
these products, which we believe would help reduce any possible BSE 
transmission through the use of ``361'' HCT/Ps manufactured using 
cattle-derived material.
    HCT/Ps that do not meet the criteria in Sec.  1271.10 are regulated 
as drugs and devices under the act, and/or biological products under 
section 351 of the PHS Act and the act. Establishments that manufacture 
such HCT/Ps must comply with the requirements in subparts C and D of 
part 1271 in addition to all other applicable regulations, including 
submission of the appropriate premarketing applications, and are 
included in this proposed rule. Information regarding the use of 
cattle-derived material in the manufacture of such HCT/Ps would be 
submitted as part of the premarket review, giving us the opportunity to 
evaluate any potential for risk of BSE transmission.
4. Medical Devices for Humans
    The Center for Devices and Radiological Health (CDRH) has an 
administrative database that FDA reviewers use to record PMA and 510(k) 
submissions. In 2002, FDA added an ``animal tissue flag'' to the CDRH 
administrative database. This ``flag'' indicates that the device 
contains or is manufactured with animal tissue of some kind; the 
species of animal tissue is not identified. The animal tissue flag has 
been recorded for 68 PMAs and 2,164 510(k)s. These numbers represent 
only devices for which PMAs or 510(k)s were filed since the animal 
tissue flag was added in 2002. They do not account for devices cleared 
or approved for marketing before that time that may contain or that may 
be manufactured with animal tissue.
    Examples of cattle material used in devices range from high risk 
tissues (such as bovine pituitary extract used as a component of growth 
media) used in a low risk clinical setting (such as a topical 
application), to low risk cattle tissues (such as collagen from cattle 
hide or muscle) used in a high risk clinical setting (such as direct 
application to the central nervous system).
    Premarket submissions for devices do not always include complete 
information about the source of animal components. In addition, not all 
devices are subject to premarket review, either because they are exempt 
from such review or because they have already been cleared or approved. 
FDA believes that it is important to help ensure that all devices that 
are intended for use in or on the body do not contain prohibited cattle 
materials. Examples of devices intended for use in or on the body 
include, but are not limited to, vascular grafts, bone fillers, 
lacrimal plugs, sutures, wound dressings, and heart valves (other than 
human heart valve allografts regulated solely under section 361 of the 
PHS Act). FDA has determined that the banning and recordkeeping 
provisions of this proposed rule are necessary to help ensure the 
safety of devices intended for use in or on the body. Medical devices 
that are not intended for use in or on the body (e.g., in vitro 
diagnostics, x-ray machines) would not be subject to the provisions of 
this proposed rule. FDA is not aware of any currently marketed device 
that is manufactured with cattle material that would be prohibited 
under this proposed rule.
5. Drugs for Ruminants
    The requirements proposed in this rulemaking would cover new animal 
drugs for ruminants. Ruminants present the highest risk of any animals 
for contracting BSE from prohibited cattle materials. Because FDA has 
other mechanisms to restrict the extralabel use of approved human and 
animal drugs that contain prohibited cattle materials in ruminants (see 
section V.D of this document), this proposed rule would only prohibit 
the use of certain cattle material in drugs intended for use in 
ruminants.
    Some drugs for ruminants may contain or be manufactured with 
cattle-derived materials. We are not aware of any drugs for ruminants 
that contain, as a component of the drug, cattle material that would be 
prohibited by the proposed rule. However, although the FDA animal drug 
database lists materials contained in drugs for animals, it does not 
identify materials

[[Page 1590]]

that are used in the manufacture of drugs for animals but that are not 
intended to be components of the drug (e.g., materials used in 
fermentation or cell culture production of drugs for animals). Because 
the FDA database does not contain information on materials used in the 
manufacture of drugs for animals, we cannot definitively conclude that 
no drugs for ruminants are manufactured with the use of cattle material 
that would be prohibited by this proposed rule. However, based on our 
knowledge of the processes and materials used in manufacture of drugs 
for ruminants, as well as the fact that very little cattle material is 
prohibited if sourced from cattle that were inspected and passed and 
were younger than 30 months old when slaughtered, we do not believe 
that prohibited cattle material is needed in the manufacture (through 
fermentation, cell culture or otherwise) of drugs for ruminants.

III. USDA/FSIS IFR

    On January 12, 2004, in response to the diagnosis of BSE in a cow 
in the United States, USDA published a series of interim final rules, 
including ``Prohibition of the Use of Specified Risk Materials for 
Human Food and Requirements for the Disposition of Non-Ambulatory 
Disabled Cattle'' (69 FR 1862). The USDA/FSIS IFR declared that SRMs 
were inedible and unfit for food and prohibited their use as human 
food. It also prohibited the use of the entire small intestine of all 
cattle in human food. In 2005, the USDA/FSIS IFR was amended, in part, 
to permit use of the small intestine of all cattle in human food if 
appropriate procedures are used to completely remove the distal ileum 
(70 FR 53043). In the Foods IFR, FDA extended similar protections to 
FDA-regulated human food and cosmetics. (See section IV.A.3 of this 
document for a discussion of the Foods IFR.)
    The USDA/FSIS and Foods IFRs will reduce but will not, by 
themselves, eliminate the use of prohibited cattle materials in 
domestic and imported FDA-regulated medical products for humans and 
drugs for ruminants. Even when excluded from human food produced in 
USDA-inspected establishments, prohibited cattle materials that have 
been denatured may leave the establishments for rendering or 
destruction. These materials, which previously have not been explicitly 
prohibited in medical products for humans and drugs for ruminants by 
FDA, might then be used in FDA-regulated medical products for humans 
and drugs for ruminants.
    Under the USDA/FSIS IFR, SRMs and carcasses of nonambulatory 
disabled cattle are designated as inedible. However, certain products, 
such as gelatin and collagen (which are both covered by the provisions 
of this medical products proposed rule) used in FDA-regulated medical 
products for humans and drugs for ruminants, have traditionally been 
produced from cattle material deemed inedible by the USDA. Therefore, 
such a designation by the USDA may not be enough to preclude use of 
prohibited cattle materials in FDA-regulated products without 
additional regulation by FDA. Furthermore, some cattle are not 
slaughtered under continuous USDA inspection (e.g., some are sent 
directly to rendering without first passing inspection). Cattle 
material from these animals, such as brains or bones, which include 
SRMs, could end up as starting material for medical products for humans 
and drugs for ruminants. If prohibited cattle materials were unlawfully 
used in FDA-regulated medical products for humans and drugs for 
ruminants, this proposed rule if finalized would facilitate FDA's 
ability to use the enforcement mechanisms of the act that apply to 
adulterated products (e.g., seizure) to prevent human or ruminant 
exposure to the prohibited cattle materials.
    Imported products also may contain the types of materials 
prohibited by the USDA, but would not fall within the scope of the 
USDA's import regulations either because of the nature of the products 
or their country of origin. Specifically, although both FSIS and USDA's 
Animal and Plant Health Inspection Service (APHIS) impose BSE-related 
prohibitions, these prohibitions collectively do not cover all FDA-
regulated medical products for humans and drugs for ruminants. For 
example, APHIS' BSE-related restrictions on imports do not cover 
gelatin for human use (beyond requiring a permit) and apply only to a 
limited number of countries (9 CFR 94.18).

IV. FDA Actions on BSE

A. Regulations

1. FDA 1997 Ruminant Feed Rule
    In the Federal Register of June 5, 1997 (62 FR 30936), FDA 
published a regulation that prohibits, with some exceptions, the use of 
protein derived from mammalian tissue in feed for cattle and other 
ruminant animals (21 CFR 589.2000). The agency published the FDA 1997 
ruminant feed rule to prevent the establishment and amplification of 
BSE in the United States and thereby minimize any risk to animals and 
humans. FDA recently proposed changes to these requirements to further 
strengthen the rule (see section IV.A.2 of this document).
2. FDA/USDA Animal Feed ANPRM and FDA 2005 Animal Feed Proposed Rule
    Following detection of BSE in an imported dairy cow in Washington 
State in D