[Federal Register Volume 71, Number 55 (Wednesday, March 22, 2006)]
[Rules and Regulations]
[Pages 14374-14377]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-2689]


=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: 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://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://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: [email protected].

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://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://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://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://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://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://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://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