[Federal Register: March 22, 2006 (Volume 71, Number 55)]
[Rules and Regulations]
[Page 14374-14377]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22mr06-7]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 530
[Docket No. 2006N-0106]
New Animal Drugs; Adamantane and Neuraminidase Inhibitor Anti-
influenza Drugs; Extralabel Animal Drug Use; Order of Prohibition
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing an order
prohibiting the extralabel use of anti-influenza adamantane and
neuraminidase inhibitor drugs in chickens, turkeys, and ducks. We are
issuing this order based on evidence that extralabel use of these anti-
influenza drugs in chickens, turkeys, and ducks will likely cause an
adverse event in humans.
DATES: This rule becomes effective June 20, 2006. Submit written or
electronic comments on this document by May 22, 2006.
ADDRESSES: You may submit comments, identified by Docket No 2006N-0106,
by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For
additional information on submitting comments, see the ``Comments''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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.
FOR FURTHER INFORMATION CONTACT: Kim Young, Center for Veterinary
Medicine (HFV-230), Food and Drug Administration, 7519 Standish Pl.,
Rockville, MD 20855, 240-276-9207, e-mail: kim.young@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
A. AMDUCA
The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA)
(Public Law 103-396) was signed into law on October 22, 1994. It
amended the Federal Food, Drug, and Cosmetic Act (the act) to permit
licensed veterinarians to prescribe extralabel uses of approved animal
and human drugs in animals. In the Federal Register of November 7, 1996
(61 FR 57732), we published the implementing regulations (codified at
part 530 (21 CFR part 530)) for AMDUCA. The sections regarding
prohibition of extralabel use of drugs in animals are found at sections
530.21, 530.25, and 530.30. These sections describe the basis for
issuing an order prohibiting an extralabel drug use in animals and the
procedure to be followed in issuing an order of prohibition.
We may issue a prohibition order if we find that extralabel use in
animals presents a risk to the public health. Under Sec. 530.3(e),
this means that we have evidence that demonstrates that the use of the
drug has caused or likely will cause an adverse event.
Section 530.25 provides for a public comment period of not less
than 60 days. It also provides that the order of prohibition will
become effective 90 days after the date of publication, unless we
revoke the order, modify it, or extend the period of public comment.
The list of drugs prohibited from extralabel use is found in Sec.
530.41.
B. Adamantane and Neuraminidase Inhibitor Anti-influenza Drugs
An influenza type A pandemic is a global outbreak of disease that
occurs when a new influenza A virus subtype appears or ``emerges'' in
the human population, causes serious illness in people, and then
spreads easily from person to person worldwide (Ref. 1). Pandemics are
different from seasonal outbreaks or ``epidemics'' of influenza.
Seasonal outbreaks are caused by
[[Page 14375]]
subtypes of influenza viruses that already circulate among people. In
contrast, pandemics are caused by new subtypes, by subtypes that have
never circulated among people, or by subtypes that have not circulated
among people for a long time (Ref. 1). Historically, many influenza
epidemics in people have originated in birds. The human influenza
pandemic of 1918 is thought to have developed in birds (Ref. 2) and the
current pandemic threat is coming from an avian influenza outbreak that
started by affecting poultry flocks in Southeast Asia (Ref. 3) with
subsequent outbreaks detected on other continents (Ref. 4). The
influenza A (H5N1 subtype) causing the outbreak in Asia has already
demonstrated the ability to transmit zoonotically from birds to people
(Ref. 3). Many experts believe the H5N1 subtype of the influenza A
virus will eventually be capable of spreading easily from person to
person, creating a new pandemic (Ref. 5).
The first line of defense for any influenza outbreak in people is
vaccination (Ref. 6). Influenza vaccines are among the most important
interventions in an influenza epidemic, but are expected to have their
optimal effect only if the vaccine is adequately matched to the
circulating viral strain. Confronted with a fast moving influenza
pandemic, there may not be enough time to characterize the virus,
develop a vaccine, distribute it widely, and administer it to enough
people to make a difference (Ref. 1). If this situation occurs in the
United States, we will become heavily dependent upon our second line of
defense, which is the administration of anti-influenza drugs. There are
currently four approved antiviral drugs, in two classes, for the
treatment or prevention of influenza A in humans. These are the
adamantanes (amantadine and rimantadine) and the neuraminidase
inhibitors (oseltamivir and zanamivir) (Ref. 7). They are not approved
for use in the treatment or prevention of influenza in animals.
Anti-influenza drugs are intended to be administered when
appropriate to people that are clinically ill with influenza to reduce
the time to improvement of influenza symptoms. In addition, they may be
administered to people exposed to influenza, to prevent clinical
illness. Although these drugs are not a substitute for vaccination, in
selected circumstances they have also been included in outbreak control
strategies. To limit the impact of a pandemic influenza outbreak it
will be critical that effective antiviral therapies be available for
treatment and prophylaxis of disease in humans. For this reason the
World Health Organization (WHO) considers these drugs critically
important antimicrobials for humans (Ref. 8).
FDA is concerned regarding the ease with which influenza A viruses
can become drug-resistant as a result of selective pressure induced by
the use of anti-influenza drugs. FDA is also concerned that the
extralabel use of these drugs in animals is likely to lead to the
emergence of resistant strains of influenza A, particularly when such
extralabel use could involve administration to large numbers of
animals. If these drug-resistant strains infect humans, it is likely
that the approved anti-influenza drugs will no longer be effective for
treating or preventing disease in those people. Therefore, FDA is
issuing an order prohibiting the extralabel use of adamantane and
neuraminidase inhibitor anti-influenza drugs in chickens, turkeys, and
ducks because, as discussed in sections II and III of this document,
the agency has determined that such extralabel use likely will cause an
adverse event and as such presents a risk to the public health. FDA may
expand the list of animal species affected as new data becomes
available.
II. Adamantanes
The adamantanes are the older of the two classes of anti-influenza
drugs, the oldest drug having been on the market for over 30 years.
Adamantane-resistant influenza viruses have been observed to emerge
readily after exposure to these drugs in both humans and animals (Ref.
9). Moreover, such viruses can be transmitted from human to human
without any loss of pathogenicity (Refs. 9 and 10). Chicken flocks in
China and other parts of Asia have reportedly been treated with
amantadine starting in the late 1990's (Refs. 8, 11, and 12).
Amantadine resistance among H5 avian influenza viruses was 0 percent in
both North America and Southeast Asia before this time. Between 2000
and 2004, amantadine resistance in H5 avian influenza viruses in
Southeast Asian flocks rose to 31 percent while remaining at 0 percent
in North America (Ref. 12). Although the H5N1 subtype of influenza A
has not yet been found in the United States, some reports indicate that
since 2003, many human and most avian isolates tested in other
countries are now resistant to amantadine and rimantadine (Refs. 9 and
10).
Genetic studies have shown that the resistance of influenza A
viruses (isolated from both birds and people) to amantadine and
rimantadine, including resistance in the H5N1 subtype, is associated
with an amino acid substitution in the M2 protein (Refs. 9 and 10).
More specifically, genetic studies have shown that adamantane-resistant
H5N1 virus isolated from both birds and people in Southeast Asia has an
amino acid substitution at position 31 of the M2 protein (Ref. 9). This
suggests that when the H5N1 influenza virus moved from birds to people
it carried with it the amino acid substitution resulting in adamantane
resistance in humans.
Birds are regarded as the main reservoir and source of influenza A
viruses for mammals, including humans (Ref. 13). Chickens, ducks,
turkeys, guinea fowl, quail, pheasants, and other birds are
susceptible, but disease outbreaks most frequently occur in chickens
and turkeys (Ref. 14). Avian influenza viruses are categorized as to
their ability to cause disease in chickens and are referred to as
having either low or high pathogenicity. High pathogenicity avian
influenza viruses identified more recently in Asia have exhibited
increased virulence for chickens with some strains causing severe
disease in ducks (Ref. 15). Reports indicate that H5N1 isolates from
Asia replicate and transmit efficiently in ducks and can cause effects
that range from complete absence of clinical disease to severe disease
and death (Ref. 16).
In the United States, chickens, turkeys, and ducks are raised
commercially in large numbers and in close confinement. Based on
surveys conducted by the U.S. Department of Agriculture, the total
inventory of live chickens and turkeys present on U.S. farms at any
given time is approximately 2 billion and 93 million birds,
respectively (Ref. 17). In 2005, there were an estimated 9 billion
chickens, 248 million turkeys, and 28 million ducks slaughtered in the
United States (Ref. 18). Each time an influenza A virus is exposed to
an anti-viral drug within an individual infected animal or human there
is a chance that a drug resistant virus will emerge. The greater the
number of infected individuals exposed to anti-viral drugs the greater
the number of opportunities for resistance to emerge. The large number
of birds that could potentially be treated at a given time within a
typical poultry production facility would result in a large number of
individual animals exposed to anti-viral drug thereby substantially
increasing the chances of selection for drug-resistant viral mutants.
In addition, mass medication of birds (e.g., via drinking water) is
likely to result in inconsistencies in dosing levels contributing
further to the emergence of resistance. Furthermore, close confinement
would likely
[[Page 14376]]
accelerate the spread of drug-resistant viruses between birds.
Due to evidence indicating that the use of adamantanes in chicken
flocks in Asia likely contributed to resistance emergence, FDA believes
that the use of these drugs in U.S. chicken flocks would likely result
in resistance emergence here as well. In addition, since turkeys and
ducks are also susceptible to avian influenza and are often raised
under similar husbandry conditions as chickens, FDA believes that the
use of adamantanes in turkeys and ducks would also likely result in
resistance emergence. Furthermore, the recent cases in Southeast Asia
demonstrate that zoonotic subtypes of influenza A, such as H5N1 that
have become resistant to the adamantanes, are still capable of
transmission to humans. Therefore, FDA has concluded that the
extralabel use of the adamantane class of drugs in chickens, turkeys,
and ducks will likely cause an adverse event and thus presents a risk
to the public health.
III. Neuraminidase Inhibitors
The neuraminidase inhibitor drugs (oseltamivir and zanamivir) are a
newer class of drugs, first approved for treatment of influenza in
humans in 1999. Although neuraminidase inhibitors appear to be
associated with a lower frequency of resistance emergence than the
adamantanes (Ref. 19), emergence of influenza A resistance to
oseltamivir during treatment has been documented in humans. For
example, oseltamivir-resistant viral strains have been detected in up
to 16 percent of children with human influenza A (H1N1) who have
received oseltamivir (Ref. 20) and recent reports from Viet Nam
describe two human patients who contracted avian influenza A (H5N1) and
subsequently died of the infection while receiving oseltamivir therapy
(Ref. 21). Oseltamivir-resistant strains were isolated from both of
these patients (Ref. 21). Although data are limited regarding clinical
emergence of resistance to zanamivir (which has been used much less in
humans than oseltamivir), mutant virus with reduced susceptibility to
zanamivir was occasionally observed to emerge in immunocompromised
patients infected with influenza virus after treatment with zanamivir
or oseltamivir (Ref. 22). In addition, in vitro studies have shown that
exposure of influenza viruses to increasing concentrations of zanamivir
have resulted in viral mutations conferring reduced susceptibility to
the drug (Ref. 23). Furthermore, cross-resistance--where resistance to
one drug means the virus would be resistant to the other--has been
observed between zanamivir-resistant and oseltamivir-resistant
influenza virus mutants generated in vitro (Refs. 23, 24, and 25).
Based on this information, FDA believes that extralabel use of either
neuraminidase inhibitor drug (oseltamivir or zanamivir) is likely to
increase the risk of emergence and spread of drug-resistant influenza
virus.
As seen with the adamantane class of drugs, concerns have been
raised that use of the neuraminidase inhibitors in poultry will
similarly lead to the emergence of influenza A virus that is more
resistant to neuraminidase inhibitors (Ref. 8). FDA is not aware of
studies that have investigated whether the use of these drugs in
poultry is associated with the emergence of influenza A virus that is
resistant to neuraminidase inhibitors. However, FDA believes the
reports of resistance cited previously combined with the evidence of
resistance to the adamantane class reported in both poultry and humans
indicate that resistance to the neuraminidase inhibitor drugs is likely
to emerge with their use in poultry.
While some reports indicate that mutations conferring resistance to
the neuraminidase inhibitors have generally been associated with
reduced viral fitness and transmissibility (Refs. 19 and 26), studies
have found that some oseltamivir-resistant influenza A strains were
transmissible among ferrets (Refs. 26 and 27). Therefore, although the
data regarding neuraminidase-inhibitor-resistant influenza A are
limited, FDA believes this data combined with data on the
transmissibility of adamantane-resistant influenza A are adequate to
conclude that if zoonotic influenza A were to emerge in U.S. poultry
and became resistant to the neuraminidase-inhibitors, it is likely that
such virus would be transmissible to humans.
The ``adverse event'' associated with extralabel use of
neuraminidase inhibitor anti-influenza drugs in chickens, turkeys, and
ducks is therefore the same as that discussed earlier with regard to
extralabel use of adamantanes. The agency's basis for prohibiting
extralabel uses in chickens, turkeys, and ducks of neuraminidase
inhibitor anti-influenza drugs is also the same as that for
adamantanes. That is, the extralabel use of neuraminidase inhibitor
anti-influenza drugs in chickens, turkeys, and ducks likely will
contribute to the emergence of drug resistance in the influenza A virus
and compromise human therapy. Furthermore, given that some reports
indicate that many of the human and avian influenza A (H5N1) isolates
tested since 2003 have been reported to be resistant to the adamantane
drugs (Refs. 9 and 10), and because H5N1 may occur in the Unites
States, it is particularly important that steps be taken to preserve
the effectiveness of the neuraminidase inhibitor class of drugs.
Therefore, the agency is acting in the interest of the public health
and prohibiting the extralabel use of neuraminidase inhibitor anti-
influenza drugs in chickens, turkeys, and ducks.
IV. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
V. Order of Prohibition
Therefore, I hereby issue the following order under Sec. Sec.
530.21 and 530.25. We find that extralabel use of anti-influenza A
drugs of the adamantane and neuraminidase inhibitor classes of drugs in
chickens, turkeys, and ducks likely will cause an adverse event which
constitutes a finding that extralabel use of these drugs presents a
risk to the public health. Therefore, we are prohibiting the extralabel
use of anti-influenza drugs of the adamantane and neuraminidase
inhibitor classes of drugs in chickens, turkeys, and ducks.
VI. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES). You may view them
between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the
Web site addresses, but FDA is not responsible for any subsequent
changes to the Web sites after this document publishes in the Federal
Register.)
1. CDC Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/flu/pandemic/keyfacts.htm,
March 2, 2006.
2. Taubenberger, J.K., et al., ``Characterization of the 1918
Influenza Virus Polymerase Genes,'' Nature, vol. 437, pp. 889-893,
2005.
3. WHO Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.who.int/csr/disease/avian_influenza/avian_faqs/en/index.html#whatis
, March 2, 2006.
4. OIE Update on Avian Influenza in Animals (Type H5); 20
February, 2006: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.oie.int/downld/
[[Page 14377]]
AVIAN%20INFLUENZA/A--AI-Asia.htm, March 2, 2006.
5. Pan American Health Organization Strategic and Operational
Plan for Responding to Pandemic Influenza (draft), September 23,
2005.
6. CDC Morbidity and Mortality Weekly Report, vol. 54, RR-8,
2005.
7. FDA/CDER Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/drug/antivirals/influenza/default.htm
, March 2, 2006.
8. Joint FAO/OIE/WHO statement: ``Use of Antiviral Drugs in
Poultry, a Threat to Their Effectiveness for The Treatment of Human
Avian Influenza,'' November 11, 2005, WHO web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.who.int/foodsafety/micro/avian_antiviral/en/index.html
, March
2, 2006.
9. Bright, R.A., et al., ``Incidence of Adamantane Resistance
Among Influenza A (H3N2) Viruses Isolated Worldwide From 1994 to
2005: A Cause For Concern,'' Lancet, vol. 366, pp. 1175-1181, 2005.
10. Wong, S.S.Y., et al., ``Avian Influenza Virus Infections in
Humans,'' Chest, vol. 129, pp. 156-168, 2006.
11. Cyranoski, D., ``China's Chicken Farmers Under Fire For
Antiviral Abuse,'' Nature, vol. 435, pp. 1009, 2005.
12. Ilyushina, N.A., et al., ``Detection of Amantadine-Resistant
Variants Among Avian Influenza Viruses Isolated in North America and
Asia,'' Journal of Virology, vol. 341, pp. 102-106, 2005.
13. Webster, R.G., ``The Importance of Animal Influenza for
Human Disease,'' Vaccine, vol. 20, pp. S16-S20, 2002.
14. FAO Animal Health Special Report: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/avian.html
, March 2, 2006.
15. Swayne, D.E., ``Occupational and Consumer Risks From Avian
Influenza Viruses,'' Developments in Biologicals, vol. 124, pp. 85-
90, 2006.
16. Sturm-Ramirez, K.M., et al., ``Are Ducks Contributing to the
Endemicity of Highly Pathogenic H5N1 Influenza Virus in Asia?,''
Journal of Virology, vol. 79, pp. 11269-11279, 2005.
17. USDA / National Agricultural Statistics Service, 2002 Census
of Agriculture.
18. USDA / National Agricultural Statistics Service, January 31,
2006 report.
19. Institute of Medicine of the National Academies, Knobler,
S.L., et al., editors, Workshop summary: ``The Threat of Pandemic
Influenza. Are We Ready?'' 2005. http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.nap.edu/books/0309095042/html
, March 2, 2006.
20. WHO Writing Committee, ``Avian Influenza A (H5N1) Infection
in Humans,'' The New England Journal of Medicine, vol. 353, pp.
1374-1385, 2005.
21. de Jong, M.D., et al., ``Oseltamivir Resistance During
Treatment of Influenza A (H5N1) Infection,'' The New England Journal
of Medicine, vol. 353, pp. 2667-2672, 2005.
22. Ison, M.G., ``Recovery of Drug-Resistant Influenza Virus
from Immunocompromised Patients: A Case Series,'' Journal of
Infectious Diseases, vol. 193, pp. 760-764, 2006.
23. U.S. Prescribing Information for Tamiflu (Roche
Pharmaceuticals, December 2005) and Relenza (GlaxoSmithKline, April
2003).
24. Jackson, D., et al., ``Characterization of Recombinant
Influenza B Viruses With Key Neuraminidase Inhibitor Resistance
Mutations,'' Journal of Antimicrobial Chemotherapy, vol. 55, pp.
162-169, 2005.
25. Mishin, V. P., ``Susceptibilities of Antiviral-Resistant
Influenza Viruses to Novel Neuraminidase Inhibitors,'' Antimicrobial
Agents and Chemotherapy, vol. 49, pp. 4515-4520, 2005.
26. Moscona, A., ``Neuraminidase Inhibitors for Influenza,'' The
New England Journal of Medicine, vol. 353, pp. 1363-1373, 2005.
27. Moscona, A., ``Oseltamivir Resistance--Disabling Our
Influenza Defenses,'' The New England Journal of Medicine, vol. 353,
pp. 2633-2636, 2005.
List of Subjects in 21 CFR Part 530
Administrative practice and procedure, Advertising, Animal drugs,
Labeling, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Director of the Center for Veterinary Medicine, 21
CFR part 530 is amended as follows:
PART 530--EXTRALABEL DRUG USE IN ANIMALS
0
1. The authority citation for 21 CFR part 530 continues to read as
follows:
Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351,
352, 353, 355, 357, 360b, 371, 379e.
0
2. In Sec. 530.41, add and reserve paragraph (c) and add paragraph (d)
to read as follows:
Sec. 530.41 Drugs prohibited for extralabel use in animals.
* * * * *
(c) [Reserved]
(d) The following drugs, or classes of drugs, that are approved for
treating or preventing influenza A, are prohibited from extralabel use
in chickens, turkeys, and ducks:
(1) Adamantanes.
(2) Neuraminidase inhibitors.
Dated: March 14, 2006.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 06-2689 Filed 3-20-06; 11:00 am]
BILLING CODE 4160-01-S